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Gabapentin is the 10th most prescribed drug in the United States and use is increasing.  In 2002, 1% of adults were taking gabapentinoids (gabapentin and or pregabalin).  By 2015 that number increased to 4% of US adults.

There are a lot of reasons that may explain the massive increase in use of these drugs.  One thing is clear, it is not because people are using it for FDA approved indications.  The FDA-approved indications for gabapentin are only for treating patients with partial seizures or postherpetic neuralgia. However, most gabapentin prescriptions are written off-label indications.

On today’s podcast we talk all about the Gabapentinoids – Gabapentin and Pregabalin – with Tasce Bongiovanni, Donovan Maust and Nisha Iyer.   It’s a big episode covering a lot of topics.

First, Nisha, a pain and palliative care pharmacist, starts us off with discussing the pharmacology of gabapentin and pregabalin, including common myths like they work on the GABA system (which is weird given the name of the drug). 

Tasce, a surgeon and researcher, reviews the use of gabapentin in the perioperative setting and the research she had done on the prolonged use of newly prescribed gabapentin after surgery (More than one-fifth of older adults prescribed gabapentin postoperatively continue to take it more than 3 months later). 

Donovan discusses the growth of “mood stabilizers/antiepileptics” (e.g. valproic acid and gabapentin), in nursing homes, particularly patients with Alzheimer’s disease and related dementias. This includes a JAGS study recently published in 2022 showing that we seem to be substituting one bad drug (antipsychotics and opioids) with another bad drug (valproic acid and gabapentin).

Lastly, we also addressed a big reason for the massive uptake of gabapentinoids: an intentional and illegal strategy by the makers of these drugs to promote off-label use by doing things like creating low-quality, industry-funded studies designed to exaggerate the perceived analgesic effects of these drug.  This long and sordid history of gabapentin and pregabalin is beautifully described in Seth Landefeld and Mike Steinman 2009 NEJM editorial.

I could go on and on, but listen to the podcast instead and for a deeper dive, take a look at the following articles and studies:

  • Gabapentin in the Perioperative setting:

Eric: Welcome to the GeriPal Podcast. This is Eric Widera.

Alex: This is Alex Smith.

Eric: And Alex, who do we have with us today?

Alex: I’m excited about this podcast. Donovan, I think this is the first time we’ve had you on. Donovan Maust is a geriatric psychiatrist and health services researcher at the University of Michigan. Oh, we should also plug your podcast. Aren’t you also part of the Minding Memory podcast there?

Donovan Yes, that’s true. Thanks for the plug.

Eric: Great. Welcome to GeriPal.

Alex: And I can see you’re a podcaster because like us, you have difficulty with the mute button. [laughter]

Eric: The bane of podcasters. We also have Nisha Iyer, who is a pharmacy specialist in pain and palliative care at the San Francisco VA. Welcome to the GeriPal podcast, Nisha.

Nisha: Thank you so much. Happy to be here.

Eric: And we have Tasce Bongiovanni, who is an acute care trauma surgeon at UCSF and the San Francisco General Hospital. Welcome to GeriPal, Tasce.

Tasce: Thank you. Excited to be here.

Eric: So we’re going to be talking about gabapentinoids, the drugs that everybody seems to love to prescribe, especially over the last decade, more and more usage. But before we get into that topic, Tasce, I think you have a song request for Alex.

Tasce: I do. It’s “We Are Never Ever Getting Back Together.”

Eric: Why are you choosing this song?

Tasce: I thought of this song as we were all trying to brainstorm something, because it just makes me laugh that she’s singing to someone about not getting back together and it’s really hard, and it made me think about perioperative gabapentin and how hard it is to get our patients off of it. And because my five-year-old loves it, so I want her to hear Alex singing it.

Eric: And this is Taylor Swift, right?

Tasce: Yes. Taylor Swift.

Eric: Yeah. So maybe she’ll listen to this podcast and give you and your five-year-old Taylor Swift tickets, because I heard that they’re the hardest thing to come by right now. It’s like gold.

Tasce: Right. Perfect.

Eric: So if anybody knows Taylor, give some tickets out to Tasce and her five-year-old.

Alex: (singing)

Eric: I got to say, you ask Alex what his favorite bands are, he’s going to talk about Beatles and stuff, but I got to say his enthusiasm level when he sings Taylor Swift just goes, it goes to level 11. [laughter]

Alex: I don’t know what you’re talking about.

Eric: Yeah, yeah.

Alex: Listeners, ignore that. Future guests, you didn’t hear that. [luaghter]

Eric: That is a perfect song, especially when we’re talking about gabapentinoids, because we are prescribing a ton of them and people are kept on them forever.

Alex: And I feel like I broke up with them back when Mike Steinman and colleagues wrote an expose about them and we were like, oh, what are they doing? They’re doing all these terrible things and we thought we shouldn’t be prescribing them and now we are doing it again.

Eric: They’re back.

Alex: We’re back together.

Eric: They’re back. So let’s start off with the basics. What a gabapentinoid is, Nisha. They affect the GABA system, right? What are these drugs? Or do they?

Nisha: Yeah, great question. So gabapentinoids typically represent two specific drugs: gabapentin, which goes by the trade name Neurontin, and then pregabalin, which goes by Lyrica. And they both get their names, which is GABA-inspired because they have structural similarities to GABA, but neither of them actually have GABA activities. So they’re not binding those receptors and acting on that pathway. Pharmacologically, they’re inhibiting alpha to delta subunits of voltage gated calcium channels-

Eric: My favorite voltage gated calcium channel right there.

Nisha: Yeah. So essentially what they do is they’re preventing the influx of calcium, and that slows the process of several different neurotransmitters in the central nervous system, such as glutamate, for example.

Eric: Yeah. I find the history particularly interesting because they developed these gabapentinoids before they knew how they worked, and it was mainly for epilepsy. Didn’t even know that they helped or potentially helped with neuropathic pain. So they call them gabapentinoids because they thought they interacted with the GABA system too, because that’s what they were analogs of, but they don’t.

Nisha: Yeah, I know. It’s probably not the first time in history where we’ve heard of a drug coming to market with one indication and then looking at all the side effects and then pulling different indications from them. But definitely gabapentin is one of those drugs that just has all of these off-label uses associated with it.

Eric: And it’s labeled FDA-approved for only two indications, right?

Nisha: Yeah.

Eric: Partial seizures and what is it, what kind of neuropathy?

Nisha: Postherpetic neuropathy.

Eric: Postherpetic neuro, and that’s the only thing we ever use it for, right?

Alex: Yeah, right. It’s good for everything, right? I thought it was good for everything.

Nisha: Well, clearly why we’re having this podcast here today. I think the only other thing I might highlight about the difference between gabapentin and pregabalin that might be relevant as we continue to talk about it is they absorb quite differently. And so gabapentin came to market much before pregabalin did, and it doesn’t seem to follow a linear absorption pattern. It’s more erratic. So if we get into the nitty gritties of the pharmacology of it, if you look at the area under the curve, as you increase dose and dose, the effect of gabapentin and its absorption doesn’t linearly follow. So after a certain point, you see a curve where you might be going up in the dose, but the effect or the amount that is absorbed is not linearly related to that. Versus pregabalin has a little bit more of a reliable absorption pattern, where as you increase the dose of it, you can pretty much expect that the way it’s absorbing and the effect it’s having on the body is linearly increasing as well.

Eric: And I heard that’s because the gut receptors, the small bowel receptors that take up gabapentin, they get saturated. So at higher doses you’re going to get less and less absorption. However, if you slow gut transit time, let’s say if you coadminister opioids, right, then you can actually increase absorption again, which results potentially in a more dangerous combination.

Nisha: Yep, absolutely. And even taking away the complexity of other drugs, they actually show that when you take gabapentin with food, it absorbs a little bit more predictably. And that’s because you’ve got other things that are absorbing simultaneously.

Eric: Any other interesting tidbits or facts that we should know as providers about gabapentin or Lyrica dosing or pharmacology?

Nisha: Not necessarily pharmacology, but something that usually gets brought up when we’re having conversations about gabapentinoids is that pregabalin is a controlled substance. And so what that means is that we are monitoring it via what, in California, we call CURES, or prescription drug monitoring programs across the entire country. And so it pops up and if you’re a different prescriber from a different healthcare system, you can still see if people have filled it, it’s limited to the amount of fills you can get in the amount of tablets or capsules you can get in a month. It’s more regulated that way, versus gabapentin is not federally regulated in that way. It’s not a controlled substance medication. There are some states that require it to be reported to the prescription drug monitoring program, and so it pops up and it can be regulated in that way, but it’s not mandatory.

Eric: Are these generic?

Nisha: Both of them are generic, yeah.

Eric: So I heard gabapentin is the 10th most commonly prescribed medication in the US. I also heard that if you look at all individuals in the US, about 4% of individuals are taking one of the gabapentinoids, 10% over 65. Donovan, why do you think that the numbers are increasing so dramatically for this drug?

Donovan Yeah, I’m surprised every time I see data, to see how commonly it’s used. In psychiatry, a lot of the anti-epileptic medications, we call them mood stabilizers and are used in bipolar disorder. So lamotrigine gets used for bipolar depression. Depakote, or valproic acid, commonly gets used for mania. A number of anti-epileptic meds get used off-label, and there’s actually decent evidence supporting their use for bipolar disorder. I think gabapentin first came on my radar as a psychiatrist because it was marketed off-label as a treatment for bipolar disorder. And for that reason, there was actually an enormous lawsuit, and the manufacturer was fined, now I think 20 years ago, in the millions and millions of dollars for off-label prescribing. So that’s kind of how it first came on my radar. I think that’s a relatively, I hope, a relatively uncommon use for it these days. In psychiatry, psychiatrists most commonly use it for anxiety disorders.

And I was actually just looking recently at a meta-analysis to prepare for you all so I sounded kind of somewhat like I knew what I was talking about. There’s actually reasonable evidence for the gabapentinoids for treatment for anxiety disorders. And there’s some, based on what we know about the neurocircuitry and neurochemistry involved in anxiety, it’s reasonable to believe that based on what Nisha laid out about the mechanism of these medications, why they might help for anxiety, but they get used for tons and tons of other things. So when I then shift over and think about being a geriatric psychiatrist and thinking about the older adult patient population, that really shifts into where these are being used for pain.

And so I think part of it is essentially, really, I think being used as a substitute for opioids, frankly might be in combination with opioids, but also potentially I think because of this pressure to reduce opioid use, they’re getting used for all kinds of chronic pain, where I would say unlike for anxiety, the reviews really haven’t supported use for chronic pain specifically, other than, say, neuropathic pain, postherpetic neuralgia, and some, what Tasce will talk about, for perioperative, perhaps, evidence per use. But for the older adult population, I think the vast majority of this is being used for chronic pain.

Eric: Yeah. Tasce, they’re using it in surgery too?

Tasce: Yes. So I know that people listening to this know a lot already about the opioid crisis and the hundreds of thousands of people who have died and the millions of dollars our country and our healthcare system have spent on treating opioid use disorder. And it has been found over many studies that a lot of that use stems from opioids being prescribed at discharge after a surgical procedure. And so surgeons really nationwide have been working hard to prescribe fewer opioids, but also to make sure that their patients aren’t going home in pain, because pain, especially for older adults, can really inhibit rehab and participating in physical therapy and these things that we need our patients to do to be able to get back to baseline, or even be improved.

And so surgeons have been really reaching for other medications and what’s called a multimodal pain regimen after surgery to decrease use or even completely eliminate use of opioids in certain procedures. And one of these medications that has been hoped to be a huge change to decrease opioid use is gabapentin. And so I think surgeons across the country have been using gabapentin in this way in an attempt to decrease opioid use.

Eric: Is there any evidence that gabapentin works in the perioperative setting?

Tasce: There are some studies that show that a dose of gabapentin in the preoperative space for especially orthopedic procedures might decrease the amount of opioids used postoperatively.

Eric: All right. So maybe not actually decrease pain, but decrease opioid use. I mean, I imagine it’s hard to figure out because maybe pain did decrease because they’re using less opioids, but the levels are the same. So it’s probably a challenging thing to try to study.

Tasce: Especially after discharge.

Eric: Yeah. You also, I believe, wrote an editorial, potentially it was a JAMA IM about maybe the post-surgical dangers of gabapentin?

Tasce: Yes. So Nisha alluded to this as well, but gabapentin, when combined with opioids, especially for older adults, can increase the risk of respiratory depression and increase the risk of all of the things that opioids already do, which is what we’re trying to get away from. So it actually can be more dangerous and is on the AGS Beers Criteria list as a potentially inappropriate medication when used in conjunction with opioids, which unfortunately, in the postoperative setting, is how we’re using it. And so it hasn’t replaced opioids. Now they’re being given concurrently.

Eric: Wait, can I go back to Nisha on this one? I’m sorry if I have a short memory, but I thought that you said that opioids slow the gut, which increases absorption of the gabapentinoids. What I’m hearing from Tasce is that the gabapentinoids may also be potentiating the adverse side effects of the opioids, like respiratory depression.

Nisha: Yeah, and that’s absolutely correct, and a different mechanism than what’s going on in the gut in terms of absorption. So gabapentin is in itself a central nervous system depressant, right? We know that some of the side effects it has, like sedation, dizziness, which are similar to what we see with opioids. And that when combined together, when you combine any CNS depressant medication with opioids, you are now increasing the risk of respiratory depression with opioids. They have a synergistic effect. And so that’s always something that will pop up at major institutes when they’re doing co-prescribing, it’ll commonly pop up as a warning of monitor for respiratory depression.

Eric: It’s great that, you know, you start these in the perioperative setting and then they’re automatically taken off after a week or two.

Tasce: Right. Obviously.

Eric: You actually did a JAGS paper on this, is that right?

Tasce: Yes, that is right.

Eric: And that’s what you found, that the healthcare system is perfectly designed to just deprescribe automatically after short periods of use?

Tasce: Right. I mean, especially for older adults. Yes. So one of the problems with opioids is that when they were prescribed postoperatively, people just continued to take them. And so there have been many studies about prolonged use of opioids. And so we thought, well, if gabapentins are supposed to be replacing opioids controlling pain, but until recently is a medication that kind of flies under the radar in terms of not being dangerous, not being a medication of misuse. And so we wanted to look at how often gabapentin was accidentally continued in a prolonged fashion. And this also comes out of my own work, when I’d have patients come back and see me for a post-op visit later than they might have otherwise, the two-month, three-month mark and they’re still taking gabapentin, why? They have no idea. So we looked at a cohort of older adults and found that after some common surgical procedures in older adults, patients who got gabapentin at discharge, a fifth of those were still on gabapentin at the 90-day mark, which is a huge number.

Alex: Nationwide population basis. That’s a huge number.

Eric: Why do you think it’s so high?

Tasce: Lots of reasons. I think a lot of reasons that we all talk about in the deprescribing space. So the patient gets gabapentin prescribed from their surgeon, they see their PCP, they have a list of medications, and they all get renewed, get represcribed. Actually, I probably don’t need to read this to all of you, but there are many, many studies looking at the problem of deprescribing in the outpatient setting. And I think gabapentin sort of gets rolled up into this. And we found that people who were more at risk for prolonged use were patients who were already more complex, so had emergency surgery, had a higher Charleson Comorbidity score. And so these patients are probably on a lot of medications already, and the easier thing to do is just continue them if you don’t know why they’re on it already.

Eric: I think it’s hard, too, because I think for a lot of providers, gabapentin is one of those chronic pain medications that people are on, you never really touch, even though if it’s not working very well. And we’ve been kind of ingrained, maybe you go up on the dose, but rarely is this medication ever stopped. Same thing with pregabalin.

Tasce: Right, exactly.

Eric: And going back to that JAMA IM study, so there was also, if I remember it correctly, so this is looking at gabapentin use in the post-op setting for those who were hospitalized, they had higher delirium rates, right? Longer lengths of stay, general worse outcomes than those who didn’t get gabapentin.

Tasce: Right, exactly. And I think this goes back to what Nisha was talking about. Any medication that is CNS-acting and then combining that with opioids is just going to create more problems. And I think we have seen in many studies with different types of medications that older adults really do much more poorly with polypharmacy. And so adding a gabapentin for postoperative pain is really contributing to polypharmacy.

Eric: Well, one thing that often comes up with polypharmacy, which I don’t think … The one benefit of gabapentin and I think pregabalin is there’s not a lot of drug-drug interactions. Is that right, Nisha?

Nisha: Yeah, drug-drug interactions, I feel like sometimes we use it as a black and white space and it’s more of a gray area because I would argue that talking about the way gabapentinoids and opioids interact is an interaction, right? But I think if we’re using it in the terms of-

Eric: Metabolism.

Nisha: Yeah. When we’re thinking about metabolism and absolute contraindications, gabapentinoids, both gabapentin and pregabalin tend to pair pretty well with all of these other different types of medications. And so that also makes them easier to access if someone does have contraindications to something else.

Eric: So it sounds like, in surgery, we’re doing potentially a lot more substitution of opioids for gabapentin.

Alex: Gabapentin for opioids.

Eric: Yeah. Sorry, gabapentin for opioids. Donovan, you’ve also looked at some of this issue in the nursing homes, another JAGS article, looking at antiepileptic prescribing in patients with dementia in nursing homes. Tell me about that.

Donovan Yeah, so I think antiepileptic prescribing, apart from being a difficult name, is kind of a misnomer, because I think what we’re talking about is in no way related to seizure disorders. And I think if you really look at how these medications are prescribed, in particular, to older adults, it doesn’t have anything to do with a seizure disorder.

Eric: They’re not using all of these meds just for all those nursing home patients with partial seizures?

Donovan No, I don’t think that that’s why they’re being prescribed. And I’ll say we, in our work, we’ve specifically excluded patients with seizure disorders, So I’m sure you all, and all the listeners know, antipsychotic use in patients with dementia is a huge issue. In nursing homes in particular, there’s been an enormous policy focus on reducing antipsychotic use. So the concern is mood stabilizers, or anti-epileptics, are quickly thought of substitutes, literally people have done surveys of clinicians of if you can’t use an antipsychotic for behavioral disturbances in dementia, what do you use? And it’s an anti-epileptic, typically, generally, actually, valproic acid. So we did this paper, Helen Kales, who now is at UC Davis, was the senior author, I think, back in 2018 in JAMA IM where we essentially looked at what happened to psychotropic prescribing.

There was this big thing called the CMS National Partnership to Improve Dementia Care, started in 2012. The whole focus was to reduce antipsychotic prescribing. So the concern is that people would just potentially shift and be using alternative medications. And sure enough, the one line that went up in our figure was for anti-epileptics. And so initially we didn’t look specifically at specific meds, ’cause as a psychiatrist and the frame of mind we were doing this paper was antipsychotics being used for behaviors going down, that means anti-epileptic. That’s really probably Depokote going up, and it’s just a substitute. So when we actually looked in a follow-up paper at the specific medications, in fact, two-thirds-ish of that antiepileptic use was gabapentin, and actually valproic acid was the second medication. And people use all kinds of things for dementia-related behaviors, but usually gabapentin actually is not generally one of them.

And so that led us to this JAGS paper where we wanted to test this hypothesis that it’s really two different, like we’re saying it’s just anti-epileptics, but really I suspect it’s two different things happening. One is valproic acid being used in patients with behavioral disturbances, which really is probably a substitute for an antipsychotic, whereas gabapentin is more likely in patients with pain. And so essentially we used minimum dataset data on, we actually had basically every nursing home resident with dementia in the US, and you can use items in the NDS to look specifically at patients who have behavioral problems, and specifically at patients who have pain. And sure enough, if you had pain, you had a higher probability risk of getting gabapentin, and if you had behavioral problems, you were more likely to get valproic acid.

So I think A, I kind of like it if my hypothesis is right and it looks like the hypothesis was right, but B, I think it also gets to just the messiness of talking about anti-epileptic, ’cause that’s not at all how these are being used. It just is how we’re describing a class of medication that has all kinds of use that really even vary by the age group. Because I think the ways we’re seeing these meds used in older adults and older adults with dementia in particular, is maybe not the same way that they’re getting used, still off-label, but for other age groups, for younger patients.

Eric: Well, I think what’s fascinating, for your sake, couple of things, is the valproic acid. One in five individuals with dementia and behavioral problems are on valproic acid and the evidence base for valproic acid for dementia behavioral issues is really zero. Great Cochrane review on this, which did not show any benefit.

Donovan Yes. So thinking about unintended policy consequences, this is the exact wrong thing that you want to have happen in response to reducing antipsychotic use. So for better or worse, for some patients where behavioral interventions are not working, there really are patients with dementia, with severe behavioral disturbances, who probably would benefit from an antipsychotic, for better or worse, out of all the pharmacological agents, they probably have the best, albeit limited evidence of having some benefit. Depakote doesn’t even have that. There’s no evidence of benefit in well-conducted trials. So sometimes when you have a Cochrane review, it’ll be like a “Oh, there aren’t enough studies. We can’t really recommend use.” But it’s not that it’s bad, it’s just that there’s not enough evidence to recommend it. In this case, they’re like, “There’s been enough placebo-controlled trials with enough patients that say don’t use them.”

Eric: And we’re still using it.

Alex: Can I just clarify for our listeners, Depakote is valproic acid. Same.

Donovan Thank you, Alex.

Alex: Same thing, yes. Got it. Good, thanks.

Eric: I wonder how much of it is just we’re substituting one sedative for another sedative … Sedating med, I won’t call it a sedative. One sedating medication for another sedating medication.

Donovan I think the truth is a lot of ways, even, frankly, gabapentin, I think some of the effect is just kind of non-specific sedation of all of these CNS active meds. So I think that’s some part of it, for sure.

Eric: Yeah. Tasce, I think you had a comment about the substitution issue.

Tasce: Yeah. I’m so glad that you brought this up and you had said substituting gabapentin for opioids and we’re talking about substituting gabapentin for Depakote. And what’s really interesting, and maybe there’s some journal editors listening, is that, so we went back and looked, so is gabapentin substituting for opioids? And looking at trends over time, while gabapentin prescribing is quadrupling in postoperative patients, opioid prescribing is also increasing. And so-

Eric: Still?

Tasce: We’re not … Yeah. Yes. That’s what I’m saying. Maybe journal editors are listening. So this is some data that Mike Steinman and I have looked at, and obviously our team. But yes, they’re both increasing. And so you think, sure, we’re swapping out one for the other. And so there are fewer opioids going out into the community, and we’re decreasing this risk of opioid use disorder, and all of the other things that have contributed to the opioid crisis. And in fact, we’re prescribing higher proportions of both.

Eric: Which is interesting, Donovan, because that’s a little bit different than yours. You saw opioids go down, but the use of gabapentin for pain continued to increase to one in seven nursing home patients with … No, no, even higher than that. Almost 30% with pain, dementia patients with pain were on gabapentin.

Donovan So the 30%, I think, was antiepileptics overall. So just ’cause I highlighted it this morning, gabapentin specifically was 14%, valproic acid was 12%, which is still out of all nursing home residents with dementia. That’s like a ton of people getting these meds.

Eric: I was specifically looking at the dementia patients with pain. I think that was actually much higher.

Donovan Oh, gotcha.

Eric: That was closer to 30, right?

Donovan Yes. For sure. And we did see specifically in this setting, actually, opioids are going down. In fact, the increase was even a little bit bigger, the absolute size of the increase of gabapentin was smaller than the absolute size of the decrease of opioids. So maybe that does suggest, in fact, substitution really is happening. We haven’t looked at the literal individual level to see if substitution is happening or if it’s more of a general kind of changing in practice patterns where new patients are getting started on different classes of medications.

Eric: Can I just take a step back here and say that, so we’re seeing that there may be substitution of gabapentins for opioids occurring in nursing home settings, people with dementia, there may be increasing rates of both opioids and gabapentinoids in the perioperative period post-surgically, and people are staying on those prescriptions for long periods of time, and we may be concerned about this, right? That’s one of the points of this podcast. What are we doing here, right? On the other hand, clinicians are trying to do the right thing, right? They are trying to do the right thing for their patients. They’re trying to treat their pain, they’re trying to take care of their patients as best they can with a limited repertoire, and feeling constrained, perhaps, by the monitoring of prescription of antipsychotics, opioids, et cetera. Is there an argument here for gabapentinoids? It may be the best of the worst options that we have, the bad options that we have. I don’t know. I’m just putting it out there.

Donovan Yeah, so, sorry, I’ll jump in.

Eric: Please.

Donovan I feel like this is a common theme. So again, thinking about behaviors, so I’m thinking about behaviors for dementia. Absolutely clinicians are trying to do the right thing. These are patients who are in distress. These are families who are in distress. That does not mean that exposing people to a treatment that really has no good solid basis, the good solid base of evidence for benefits. But we know that that patient can experience all the harms, regardless of whether the patient has postherpetic neuralgia, for which gabapentin has an FDA indication, they can still experience all the harms from that medication. And so I’m very sympathetic and understand the challenge, but I think we need to think more broadly about what providing care means, and what that care can look like, and not be limited to defining that care as providing the patient with a pill, where everything that we know for many of these indications and medications is that the harms outweigh the benefit. I understand that it can be a hard place clinically. I don’t see how that justifies exposing patients to something that, in all likelihood, is going to cause them harm.

Eric: Tasce, in your population, the surgical population, acute pain, again the evidence isn’t that it actually improves pain, but maybe a decreases opioid use. Do you still use it? Gabapentin?

Tasce: I personally don’t, especially not in older adults. And I agree with what you said and completely agree with what Donovan said. I think people are really trying to do the right thing, and as surgeons, really seeing what opioids have done to people, to our patients in our country, people are trying to find something else. I think the problem is, as you said, it might not actually work that well and it might not really be substituting, which was the whole point in the first place. And the combination of the two has even worse adverse effects than either one on its own. So it does make you wonder, and I think more studies would need to be done on this, but it does make you wonder what the best pain medication is. In the acute phase of pain for older adults, it might just be low-dose opioids.

Eric: Yeah. Nisha, question for you. We’re talking a lot about side effects of these drugs. When I think about the gabapentinoids, pregabalin, gabapentin, do they have the same side effect kind of profile, and what is it?

Nisha: Yeah, good question. So both gabapentinoids, gabapentin and pregabalin, carry the most common side effects we see are the sedative side effects. So sedation, dizziness, loss of balance. When I think about our older population, I worry about a risk of falls especially. And then the other one that really comes to mind, obviously if you look up on these package inserts, you’ll see a laundry list of side effects, I’m highlighting more pertinent ones, is for folks with cardio comorbidity. So I’m thinking heart failure. The gabapentinoids are known to maybe cause a little bit of edema and fluid retention. And so that’s something to keep in mind, since we do have quite a prevalent population of elderly folks with cardiac comorbidities. When you think about comparing gabapentin to pregabalin, right? There are no new side effects or unique side effects to one of them that the other doesn’t have.

But what they found is that pregabalin tends to have a lower incidence, or occurrence, of those side effects in theory when they were marketed. That’s what a lot of the papers say. There have been a lot of papers that have come out since then that have shown that folks who had a suboptimal response in terms of neuropathic pain to gabapentin who switched over to pregabalin got better response with no increase in side effects. So that shows you that maybe they’re comparable there. And then they’ve done some research where they saw patients who had really intolerable sedative side effects from gabapentin tried to convert them to pregabalin, and they found that there wasn’t really a clinical difference in the folks who were tolerating pregabalin better. So essentially if you were not tolerating gabapentin, switching to an equivalent dose of pregabalin didn’t really help them. So I think the jury is still a little bit out on if there’s a real difference, but there supposedly is supposed to be a milder side effect profile with pregabalin.

Eric: Although pregabalin, right, more misuse of pregabalin out in the community. Is that right?

Nisha: That’s such an interesting point you bring up, because I think that pregabalin “misuse” is easier to catch because it’s so highly regulated, because it’s a controlled substance medication. If folks are requesting early refills, you’re able to catch that a lot easier than with gabapentin, where folks get 90-day supplies and oftentimes they’re taking nine tablets a day, so you’re thinking they’re getting bunches and bunches of meds. It’s harder to catch if folks are misusing that. And there’s actually a couple good papers that focus on gabapentin misuse and how it’s probably underreported for that reason. So I don’t know that I would think that pregabalin is more misused in this community. If anything, gabapentin is actually a lot easier to access and buy illicitly because it’s just not as regulated.

Eric: I guess the other question is how should I be thinking? Because you mentioned earlier studies showed this, later studies showed this. How should I be thinking about all of these studies, like postherpetic neuralgia. There’s a great Cochrane review on it that showed [inaudible 00:38:38] of six or seven for moderate decreases in postherpetic neuralgia pain. However, 50% of people will not get a therapeutic response. So half the people will not benefit from gabapentin. But it comes in the context, Donovan, you mentioned this, of illegal marketing practices for at least a couple decades by the original producers of both the Neurontin and Lyrica, and Pfizer, which bought out the original producer of Neurontin, billions of dollars in fines to Pfizer alone for illegal marketing practices, which included not publishing negative studies. Very explicitly in the court documents, they had a policy of not publishing negative studies. So you do two studies, one may be positive, one may be negative, only the positive one gets published. How should we think about the evidence for the effectiveness of this drug, given that we do know there was explicit illegal activity in its marketing and publication?

Nisha: Such a difficult place to be that I’ll just want to take a moment to highlight that we should never be put in this position. We should be able to trust all the data that comes from our governing board. So obviously a much bigger conversation that is beyond the scope of our podcast today. But we should highlight that. Now that we are in this position, when I think about data for pain management specifically, I feel like yes, there’s value to it. We want to see in general what is helping folks and what isn’t. But also just in my limited practice, and I’m a relatively new provider, I’ve just noticed that pain management is so individualized. Our bodies are just so complex, and pain medication options, while they sound like there’s a huge laundry list of them, when you break them up by class, we really don’t have that many great options.

We’re really just, I think Donovan said this earlier, weighing the benefits against the harms. And so really I think when we don’t have great data to guide our decision-making, when we have folks who have some sort of neuropathic pain, I say if we try a low dose of pregabalin or gabapentin and we just monitor them really closely, we refer them to specialty services where they have the capacity to be seeing the patients with close follow-up one to two weeks during titration period. And if we’re seeing a lot of side effects, we pull it off and we taper it off if they’re on a higher dose, and if we see that they’re helping them, then we continue them and just employ our risk mitigation strategies with close follow-up, short fills, monitoring for drug interactions, and then monitoring for side effects is the way I would approach that.

Tasce: I think something else that got said that I just would love to highlight, thinking about our healthcare system as a whole, is this reaching for pills. So someone has pain and we figure out which pill is going to work or which three pills are going to work. And I think what’s missing from the conversation in healthcare more broadly is what are all the other things we can do for patients with acute pain and with chronic pain, which I think are two very different things. And so squishing gabapentin into this conversation is really hard because there’s all these different types of pain that people have and different uses for gabapentin. But I think, as Alex asked earlier, how are we treating the patient in front of us and not just reaching for which medication is least bad?

Eric: Yeah, I mean, similar with dementia-related behaviors, right, Donovan? Very few people make a profit on non-pharmacological treatments for dementia-related behaviors or for pain, but there are billions of dollars in potential profit by prescribing a pill.

Donovan Yeah, on the pain front and the anxiety front, there’s lots of evidence around the benefit of specific psych therapies, which is a whole other conversation for how and why that’s such a challenge for folks to have access to. But it’s pretty clear that there are definitely some evidence-based, non-pharmacological treatments, also including dementia behaviors, that are definitely out there and work. It’s a matter of having … Something we won’t solve on a podcast, of having a system that’s set up to actually be able to deliver and provide that kind of care to people is, yeah. Writing a prescription is so much simpler.

Alex: Last question from me. Oh, Eric’s going to get to the magic wand question. Last question from me is, Donovan, can you plug your podcast? What is Minding Memory and why should our listeners listen to that podcast?

Donovan Oh, sure. So Julie Bynum is the PI. So this comes out of work that was part of a center funded by the NIA on population research related to dementia. I work with a guy named Matt Davis, who’s in the School of Nursing at Michigan, on what’s called the external resources core. And when we were working on this proposal, we were like, “Hey, let’s propose a podcast. That’ll be super cool and innovative.” And now it seems like everyone and their brother has a podcast. But anyways, we started a podcast.

Eric: It’s mandatory here at UCSF to have a podcast, by the way. [laughter]

Tasce: Not everyone sings though.

Donovan No, we definitely don’t sing. And the whole goal of the Center is partly to sort of help expand the researchers and people who are interested in dementia. Usually what it ends up being is we pick a paper of someone that we just want to talk to and chat with them. In our first season, a lot of what we talk about is using national surveys like NHATS or HRS, and so we actually had one of the people from HRS come and they administered the TICS, which is the telephone interview for cognitive assessment. I got to take it as part of the podcast.

Eric: Did you pass?

Donovan So that’s been fun. I did pass. I did pass. Although it was very tricky because their delayed recall … Like when I give somebody the MoCA, I say, “Okay, here’s three words. I want you to repeat them and then I’m going to ask you them in a couple minutes.” So apparently for the TICS, you don’t tell people that, so you just have them register this list of words. And then she came back a couple minutes later and was like, “Do you remember those words?” I was like, “I do not, because you didn’t tell me that you were going to … [laughter]

Eric: Yeah, the performance anxiety on air too. The idea of failing on air would destroy me.

Alex: I’ve never messed up a song. I don’t know what you’re talking about. [laughter]

You can’t even get the mute button right. [laughter]

Donovan So it’s Minding Memory.

Eric: Thank you. Minding Memory, you can find it on any podcasting app?

Donovan Yes you can.

Alex: And I’m loath to admit it, but they do have better music because they got it from [inaudible] Langa’s son, who’s a professional musician.

Donovan We did.

Alex: However, it’s beautiful music, but it’s the same every podcast. We have variety!

Donovan It is. We don’t do our own music. And I have to say, last night, for the listeners who don’t know, I don’t know if Alex always did this, but we got an email yesterday that he was looking at the song for the podcast today. And A, I’m super impressed that he came up with that so quickly. But also, I just breathe a great sigh of relief that we did not choose to do anything like that for ours because it would’ve been too stressful to have to do that.

Eric: All right, real quick, I’m going to ask the magic wand question. If you had a magic wand, you can change one part of this equation, whether it be clinician behavior or something else, what would you do? Donovan?

Donovan I’m actually going to kind of answer maybe for the post-surgical issue, I would like to have inertia be less of a force, so it was easier to stop.

Eric: Okay, Tasce?

Tasce: I agree. So I’m going to use my magic wand to give a small caveat, which is not all surgeries are the same. And so there may be some surgeries in which gabapentin might be appropriate in the short term, just not surgery that I do.

Eric: Nisha.

Nisha: I think if I had a magic wand, I would make sure that every healthcare system had really good transitions of care and had capacity to have one-week follow-ups to do overall deprescribing.

Eric: I love it. And I think if Alex had a magic wand, he would choose to play more Taylor Swift right now.

Alex: (singing)

Eric: Yeah, you just got to sing that after every surgery. Well, exacerbate their pain. Donovan, Tasce, Nisha, thank you for joining on the GeriPal podcast. It was a blast.

Nisha: Thank you.

Donovan Thanks for having me.

Tasce: Thank you.

Eric: And we should definitely get back together soon. And thank you to all of our listeners for supporting the GeriPal podcast.

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