Baa's and Bleat's - The AASRP Podcast
Baa's and Bleat's - The AASRP Podcast
Flunixin Pharmacology with Dr. Joe Smith
Join us for this discussion about the pharmacokinetics of subcutaneous administration of flunixin meglumine in goats with Dr. Joe Smith from the University of Tennessee. The primary paper discussed is titled:
“Pharmacokinetic Parameters and Estimated Milk Withdrawal Intervals for Domestic Goats (Capra Aegagrus Hircus) After Administration of Single and Multiple Intravenous and Subcutaneous Doses of Flunixin Meglumine"
Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248982/
Please remember that flunixin meglumine is only labeled from IV or intramuscular injection and should not be given subcutaneously without the written instructions of a licensed veterinarian in the United States. Use of alternative drugs such as meloxicam is strongly encouraged when IV injections cannot be administered. Practitioners should request withdrawal guidance from the Food Animal Residue Avoidance Database (FARAD) before recommending extra-label administration of a medication.
To submit a FARAD withdrawal request follow this link: https://cafarad.ucdavis.edu/FARMWeb/
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All right, I'd like to drop a disclaimer here. Since this episode has covered topics pertaining to extra-label drug use, no part of this discussion today should be considered a treatment recommendation from me, Dr. Smith, or the American Association of Small Ruminant Practitioners. Banamine or FluNixin is a prescription medication that requires veterinary oversight. So for producers, that means any and all questions should be about how to administer this drug should be directed to your veterinarian. For veterinarians, you should remember that the subcutaneous administration of banamine, although it's new and exciting, and we're really excited about the work that Dr. Smith has done, it's still extra label. So when making treatment recommendations to clients, it is important to consider federal and all other laws and regulations regarding extra label drug use that apply to wherever you're practicing. Here in the United States, that should include a request to FARAD for withdrawal recommendations. All of this is to ensure that the food products from the animals that we treat are safe for human consumption. Thank you again for listening. If you have any questions, please feel free to reach out. Good morning, and thank you for joining us today for Boz and Bleats, the American Association of Small Ruminant Practitioners podcast. Today we'll be talking to Dr. Joe Smith from the University of Tennessee. It's great to see you, Dr. Smith. Thanks so much for joining us.
Joe:Well, thank you for having me, Dr. Lowry.
Sarah:So I'd like to start with just a little bit of a history lesson. Give us a little insight of where you've been, how you got here, a little bit about your background.
Joe:Absolutely. I am originally from Southwestern Pennsylvania. I went to undergrad at Penn State. And for me, I think it's very neat to be able to be on this podcast because I've had uh Dr. Van Son as an undergrad student, as a veterinary student, and then after my DVM, I had a program the Penn State Extension ran for dairy veterinarians. So it's cool to be on the same program that he's been. I went to vet school at Ohio State, and after that, I worked in private practice for a few years in a dairy mixed practice just south of Lake Erie. So we had a clinic in Pennsylvania and a clinic in Ohio. From there, I kind of realized my interests were more on the individual large animal. And so I went and I did a residency in large animal internal medicine at UC Davis, California, and it was very different than everything I'd seen before with respect to diseases and conditions, and had a very good three years there. That's where this uh project came to be. That project kind of sparked an interest in pharmacology for myself. And around the third year of my residency, there was posting it Iowa State for a pharmacology resident slash PhD student. So I applied for that. Shortly after applying for it, but before I got to Iowa State, there was a faculty member in Food Animal Hospital that I think retired a little bit earlier than I anticipated. So I was on my, I think Monday I started grad school. Thursday they had me applying for a faculty position, and I had a very unique role where I was three-quarter time faculty and then part-time pharmacology resident, part-time PhD student in Iowa State. So it was a very, very good school, a very good experience for me. After I finished my PhD, I moved to the University of Tennessee, and I am faculty here, and I spend some of my time in the farm animal hospital, and I spend some of my time lecturing. And so I'm our clinical pharmacologist as well. I teach our pharmacology course, and as well as you know, performing research, and majority of my research focuses on small ruminant pharmacology.
Sarah:Yay, I love anyone whose focus is on small ruminant anything. Again, I say this with every single person I talk to, but I just love how we follow each other around the country. I also went to UC Davis. I also have a master's from Iowa State. You know, Pennsylvania is a hop, skip, and a jump from western New York. So I just love how we cross paths all the time. Okay, let's jump in. So today, Dr. Smith and I are going to be talking about a paper that is titled Pharmokinetics Parameters and Estimated Milk Withdrawal Interval Intervals for Domestic Goats after administration of single and multiple IV and sub Q doses of Flu Nicen Megalamine. So anybody who does anything with um goats is just over the top excited about this paper. I'm just going to give a little background about flunixen, just kind of more for our producers, obviously, just so we're all on the same page. And obviously, Dr. Smith, correct me if I if I say anything wrong here. And I also may absolutely slip and call it vanamine. Banamine is the name brand. Flu nixin is the actual name of the medication, but I tend to put those two interchangeably. So flunixin is what we call a non-steroidal anti-inflammatory drug. In human med, that would be like advil, aspirin, something like that. It's by far the most common medication we use in ruminants for pain and fever. At least I do that in maloxicam, but lots and lots of anamine. In the past, we were always taught as producers that it had to go IV. There were no other ways. This being said, most of my clients, and I assume many people listening, don't give it IV because it's just hard for non-practitioners to do that. And I would say most of my producers probably give it IM. As most of us know, there's a transdermal option for cows. But I my understanding was that this was not a good thing to do in small ruminants. They have thinner skin. We didn't have good research of how that was absorbed or what kind of reactions they would have to that. A big part of this picture, one reason we've been very hesitant to give it subcutaneously is because of the reactions that we've seen in horses over the year, literally like sloughing their skin. Would you have it? Would you add any to that background on flumixin?
Joe:Uh that's fairly accurate, Dr. Lowry. I think the you mentioned flumixin and meloxicam being the more common NSAIDs or non-steroidals, and that's absolutely true. One of the questions that I had when I was presenting this work before is why wouldn't you just use meloxicam? Because it could be given oral and there's no needle. And there's definitely circumstances where we can use meloxicam instead of flumixin. But as you mentioned, I think clinically we probably have a better like antipyrexic effect for fevers with flunixin and meloxicam, even though I do think maloxicam is definitely probably better for long-term use for like arthritis or that type of pain. There has been, so the study was done before the transdermal formulation came out, even though it was published afterwards. And there has been work to show that in meat goats the bioavailability is quite low, it's less than 25%. In alpacas, it's less than 25% for the transdermal formulation. But I think recently the group at NC State just got a grant to investigate the transdermal formulation in sheep. So it may have an application there based on their pilot work, which I'm looking forward to see what they have. And absolutely, I have clients that I feel could give an injection intravenously, but it can be very challenging, especially if it's you know a person giving it by themselves on the farm. And so the goal with this project is we just want to look at a route that we felt would be a little bit safer. And keeping in mind, like what you mentioned with the equine side of things, we've all seen, or if we haven't seen, there's you know multiple cases out there of horses that get phonixin IM, and even though it's still labeled for horses IM, the nature of the drug in the muscle can cause a myositis, can cause a little bit of inflammation. And there's some horror stories out there where it wakes up clusterdial spores, and we'll just see huge myocitis, and they'll have to do fasciotomies in the skin to get air in there because it's an anaerobic organism. So our goal here was to look at a commonly used drug that we knew could you know impact small ruminant health and welfare and see if there's an alternate route to give it that might be a little bit more you know convenient and increase compliance.
Sarah:Yeah, that's I I find talking about the meloxicam versus banamine, you know, equine people think everything should go oral, and ruminant people think everything should be injectable. So when I introduce my clients to meloxicam for like long, I have I mostly work with pets. And so, you know, I have those geriatric goats, those geriatric camelids, you know, I even like try to baby along CAE positive animals through the end of their life with pain meds for many months, even years. And so when I introduced them to meloxicam, they're like, what oral? You know, that's just I feel like that's not a common thing. But yeah, maloxicam is great and a little bit safer for for the rumens for sure. Okay, how so just back up a little bit. How did you just was it just you're working with small ruminants and our need for this research? How did you come upon this study and what kind of prompted you to look at this?
Joe:So I I've always had an interest in pharmacology, and I think that goes back to vet school. So I've had to review that quite a bit for that reason. And I think that's one of the challenges and one of the reasons why I like small ruminant practice so much, is it looks like we're always looking for creative solutions. Like we don't have answers and information for this drug and this species, but do we have it for a similar species? Can we extrapolate from there? Um, I was very fortunate when I was at my medicine residency at UC Davis that I had a very um supportive faculty team. And originally I had the idea, you know, could we give this injectable flinuxin product orally? And we had talked about that, but I think from the mentorship I had, they kind of pointed out to me that I wasn't aware that much more people were giving it like I am or sub Q. And so that probably would be more relevant data. And so there is an oral formulation of Flinuxin available in other countries, but it's very different. It's a granule, and it actually has properties in that that I think would enhance absorption in the rumen, whereas the injectable formulation most likely would not to that extent. So I I think I had a combination of an interest and a you know mentorship that was I was fortunate to guide me for this project.
Sarah:Nice, nice. All right, well, let's jump in.
Joe:So one of the challenges we have, and and just for the the audience, is we don't have a lot of drugs that are labeled you know for goats in in the United States. And so when we use a drug, it's not labeled, we're using it extra labely. And when we have a drug, we're using on label on the labeled species, labeled throughout labeled dose, we have what's called a tolerance if it's a food animal. And that's basically a concentration that if we're below in the final food product, whether that's milk or meat, it's considered safe. If it's above it, um, it's considered potentially dangerous for the human population for food safety purposes. And so what we were looking for with this study was to try to determine those levels of milk. We also wanted to get a sense of the pharmacokinetic parameters of the drug. And these are things like the maximum concentration, the time to maximum concentration, clearance, which is the unit of blood cleared by an amount of the substance per unit of time, volume distribution, which is just how the drug penetrates through the tissues, and those types of things. Elimination half-life would be one. And to do those studies, we have to get a group of animals, we give them the drug at the same time, then we collect blood and we analyze it. And this study started as one uh trial. It actually started as trial three, the single dose, where we would give it IV and sub Q, and then collect blood and milk. And then we realized clinically we we often don't give flunixin for just one dose. We often give it for multiple doses. So we mimicked what we did in the hospital where we give 1.1 megs per gig twice daily for three days, and so that became trial four. Some of the pilot information that helped us plan this was trial one and trial two. And trial one was pregnant goats, and we looked at sub Q and IV, but it was just plasma. And for all these studies for plasma, we looked for both the concentrations of flumixin, which we would call the parent drug, as well as the five hydroxy metabolite, which we would call the marker residue. And going back to the earlier comment about tolerance, um, tolerance is based on the concentration of either the parent drug or the marker residue, basically, whichever one is in there, in the the tissue or the milk, and whichever one you understand the relationship of how it gets there the best. And so, five-hydroxy flinuxin is the marker residue. So that's what they would be looking for with respect to tolerance if we're talking about flinuxin and dairy cattle. I'm sorry, I got off track a little bit there.
Sarah:That's fine. I think this is all important information about what you looked at and why. So keep telling us about what was important.
Joe:One of the questions that might come up is you know, if we were looking at sub Q, why did we investigate IV as well? And to determine the absolute bioavailability, you need to be able to compare an extravascular route, so in this case, you know, the subcutaneous administration to the IV route. And we compare the area under the curve, which is another one of those parameters, but it's basically just the total exposure of the drug to the system. And that's how we can determine the bioavailability. And so looking at are the parameters similar for each route? Is the bioavailability similar for each route? And ultimately, are the you know, what are the concentrations of the milk were kind of the goals to drive this one.
Sarah:I also think a huge takeaway for for all of our listeners who are terrified to give it under any route besides IV is that you also watch the injection sites, right? So the same person every day was looking at the injection sites and making sure there wasn't like a serious negative reaction. So how well it's working, how long it's working, but also like is there a negative effect that many people are worried about?
Joe:Yeah, we had a very in-depth scoring system for this, and essentially we we didn't really get to use much of it at all because we did not have much reactions at the sub Q injection sites.
Sarah:Did they look at the IV injection sites also, or was it just the sub Q sites?
Joe:We weren't scoring the IV injection sites. Um the one thing about the study that I was very fortunate is the you know, the goat barn at EC Davis, especially the dairy goats, is impeccably managed. And for this study, for most of the studies I've done since on a shorter acting drug, I'll I'll place a catheter and I will, you know, I'll give my drug by whichever route, but then I will have one catheter and the drug is a brain that is purely for sampling. Like if I give an IV drug, I'll give that by another catheter. For this study, the way the management team was, the study team was, we did everything with vacuiners and off-the-needle injections. And I don't think that would necessarily be possible for all PK studies, but if the GoFar manager at EC Days at the time, Jan Carlson, just had impeccable management for you know her operation there, and we were able to do that. So we didn't really score the IV injection sites. We were paying attention because we were using vacuumers just to if we felt we saw swelling in the vein, and and that really wasn't a you know concern that we had at the end of the study, you know, based on what we saw.
Sarah:Great, great. Another just question I had before we jump into the results: why did you pick the thoracic region to give the sub Q shots? Is there a reason versus like the neck?
Joe:Yeah, it's a great question. That was an initial discussion that we had, and I think for if we were just gonna do a single dose, the neck would have been fine. But the concern that we had is that if we want to evaluate the safety of the injections, we would have to come back and look at each site. So each site would have to be distinct. And so we actually had three different sites on the left side and three different sites on the right side, and those corresponded to where we gave the individual injections.
Sarah:And so we actually laid you just need a bigger area, basically.
Joe:Yeah, a bigger area because we wanted to avoid giving a subcutaneous injection at the same site multiple times because there potentially, you know, we didn't know there could have been inflammation or something like that that would have interfered with absorption. And it it seemed reasonable at the time. And you know, afterwards, you know, we didn't really see any swelling or reactions there. And we had put those areas, we had labeled them with the Sharpie, you know, we had a caliper ready to measure them, but unfortunately, we just didn't really see that. Well, fortunately, excuse me, we didn't see that degree of swelling or reaction from them.
Sarah:Yeah, no, I get that. Us as doctors, especially when we're looking for disease, we get really excited when there's disease and issues. It's okay, it's a it's a byproduct of our profession. Okay, so let's let's jump in. The results are like just so exciting, honestly. This this isn't like our first podcast where I wanted to come away crying, talking about stones in the bladder. This one I I uh finished the paper and I was I was super excited.
Joe:I think we can start with the pharmacokonnect parameters for trial one and trial two.
Sarah:Okay.
Joe:And so these would have been the pregnant does that were not lactating and then the young does that were not pregnant. And there's all kinds of pharmacokonnect parameters in this paper, but I think some of the things that were interesting for me was the elimination half-life. And so that's for an IB administration, all of the half-life would technically be the elimination phase, but for non-IB administration, there's going to be a component of absorption where the concentrations build up and the plasma, and then the elimination. And so when we were just looking at the elimination component of the half-life, it was very similar around those groups. So I think for trial one, for IB, it was a little more than two hours. For sub Q, it was a little bit more than four. And then for trial two, we were looking at like three hours for IB and actually a little bit quicker, about 2.8 or three hours for sub Q. The other thing that was exciting for me was the bioavailability. And so, again, this would be comparing area under the curve, which I just think of that as a quantification of the total exposure of the drug to the animal. To calculate that, you actually need to use the trapezoidal method with calculus, which thankfully I have a program that does that for me, and I don't have to dig up calculus. But the bioavailability of flunixin was, I think, around 89% for that first trial when given by the subcutaneous round, and about 94%. So, I mean, that essentially shows us that we probably don't have to alter the dose. And that was one of the issues with the transdermal flunixin in meat goats, was this the bioavailability was so low, I think it was like 24%, that they would have to give like four times the cattle dose if you're looking at it mathematically, and that might actually be more area than what the goat would have to absorb it. So that was exciting for us to see. Okay, the bioavailability is similar, the elimination is similar. Now, one of the things that's important to keep in mind is pharmacokinetics and pharmacodynamics, while they're related, they can be very different things. And so it is encouraging to see similar levels, similar elimination, similar bioavailability, but we were not looking at like the effect of this on pain or anything like that. What we were looking at pharmacodynamically was just the milk concentrations. So it's certainly promising to see similar pharmacokinetics between these different routes. And then when we moved to trial three and trial four, which were the lactating dairy goat dose, the elimination half life was very similar. I think it was like four and a half hours and like 3.8 hours for the first round, which would be the single dose. Then for the multiple dose, it was a little bit more than four hours and around three hours for IBP. Versus so few. So again, we were seeing that was pretty similar. The bioavailability in the lactating dose was a little bit lower. It was about 74%. But I still think like clinically, that's probably not warning that much of a dose adjustment, if any, at all. And then it gets a little bit challenging to do bioavailability on multiple dosing just because the area under the curve gets changed quite a bit from each dose. So we we didn't do that for that study. But again, seeing similar bioavailability and similar elimination, I think is definitely encouraging.
Sarah:Yeah, so I, you know, I hope you all of you look this paper up, but it is, you know, it the IV method, it's higher faster, but very quickly, sub Q is right there at the same level, you know, working. So I mean, my thought as I was looking at this is like, okay, if I'm treating, you know, like a polio goat that's down and I want it to work now, a bloat goat that I want it to work now, maybe I'll still go IV. But, you know, if it's something like a limp, you know, the stupid goat jumped over the fence and twisted its ankle or whatever, like sub Q is fine, you know. So, you know, I always think about this as like, how are we as the doctors' boots on the ground? And I know in the clinic, you guys are too. You know, what is our kind of takeaway? And so I think it was, you know, very obvious that this works great. Like, there's there's no reason um not to do this. One thing, and I was gonna say this later, but I just still want to throw it out there for our readers. These takeaways are great, but this is still extra label. And so just we need to keep in mind that just because the papers come out, the labels haven't changed. And so we still, especially with the food portion, need to, you know, be very diligent about what we're telling our producers to do. This hasn't, you know, it hasn't changed the labels, so we still have to be very conscientious about our food food products here.
Joe:And that's that's a great point, Dr. Lowry, because like we did try to estimate you know later in the study what a milk withdrawal would be for a dairy goat. Um, some of that was based on it being extra label. But the recommendations for extra label withdraw, like if we would reach out to the uh Fair Ad or the Food Animal Residue Voice Data Bank, I believe those recommendations are just for that case that you reach out for. And you know, this paper was published a few years ago. The analytical technology to detect drugs is only getting better as time goes by. And so there would be the potential, you know, while our model, you know, I feel is very solid with the recommendations we have for withdrawal. If you have, you know, if you're doing this with a client regularly, doing a Fair Ad request may not be a bad thing, uh, just in case there's been new information. Because, like you mentioned, it's all extra label. And when we use a drug on label, as long as we're below that tolerance from a regulatory standpoint, the product is safe. But when it's used extra label, any detectable residue is considered a violation because it's a zero-tolerance situation.
Sarah:Yeah, and I'm sure Ferret is pulling this paper up and looking at your research a lot. You know, that's what they do, that's how it works. Um, one thing I whenever I'm preparing for these podcasts, I like to look at, you know, so a lot of us use plum, right? Like that's our our kind of our drug handbook. And looking at flu nixen, I which I never do because I just, you know, I use it so much, I have it in my brain, what I need, but they have a dose for sheep and goats for IV, IM, and oral, which I thought was and transdermal, which I thought was really interesting.
Joe:Yeah, I think the the oral may be based on uh the granule formulation.
Sarah:Okay, from another country.
Joe:I'm not sure if that's based on giving the injectable formulation orally. I I do try to keep up on this, and I don't think I've seen that that published yet, but there's always, and especially if you're dealing with sources like Farad, they always have studies they're doing internally based on the questions they get. So there could be more information out there now, too.
Sarah:Yeah, yeah. So sorry, I'm getting off track from the paper. Let's get back to it here. What do we need to take away from this paper?
Joe:Um we know one of the things that you mentioned, like if we needed to give Linuxon right away, we could give it IB. And you know, if it was something we felt we could wait a little bit, we could give it sub Q. And that's not that's still how I use in the clinic. Like if I'm giving this drug, you know, perioperatively, I give it IBE so I have it on board before I go to surgery. But the time to maximum concentration or the T max with sub Q, it wasn't you know instantaneous like it was for IVE, but it wasn't that long. I believe it was just a little bit more than an hour for most of these studies. So it does achieve that max, its maximum concentration a little bit um later than IV. Those maximum concentrations are different, but that's not uncommon when we're giving a drug by an IV route versus an extravascular route. The one thing that impressed me when I was putting all this data together in the paper, there's time versus concentration graphs for like the plasma uh flunixon and plasma 5 hydroxy flunixin concentrations for each of the studies, and they are are very, very similar. Um we have the differences because IV, there's no absorption phase, it's just all elimination, and for sub Q, there's an absorption phase. But after we get past that first hour, like the the curves and the from a time versus concentration perspective are almost identical. And I I think that kind of tells the story here that if you have a scenario where it can't be given IV, you know, sub Q probably will you know be effective and pharmacokonnect parameters and concentrations reaching the plasma perspective.
Sarah:So in your hands, just bringing it back to our producers, are you would you be using Flu Nixon at the 1.1 MG per kig, like every 12 hours? I tend to do the 2.2 every 24. Do you do you have an opinion on which of those is probably more beneficial?
Joe:Uh I normally think of the 2.2 mgs per kig as our total daily dose. And in the in the hospital in the hospital setting or the referral hospital setting that I'm at, I often see animals that you know, maybe they've initially been worked up already, um, they're not working out the way the referring veterinary and the client had hoped, so they sent it to us, or maybe we're just seeing like a more complicated case. And so I'll typically try to go 1.1 mig per kig every 12 hours if I can, just because I think with the adverse effects of this drug in a population that might be a little bit more stressed, that might be warranted. Now, with that said, do I have circumstances where I have to use 2.2 MIGs per kig once daily instead? Absolutely.
Sarah:Okay.
Joe:It might be might be some of that academic bias that I've accumulated over the years, but I don't think necessarily one is right and one is wrong, depending on the circumstance. And certainly, if I'm concerned about the welfare of the animal and the client can only give it once a day, then that's what I'm gonna try to set up so that the animal gets the drug it needs.
Sarah:And I typically recommend like three, four days max because we worry about ulcers. And I know that was not part of your studies. Um what do you think about that? Is that a legit thing, or do you think we overworry about that?
Joe:I think three, you know, three days and then being concerned about ulcers is warranted. I've had um you know, cases I've managed before earlier in my career where I've kept on flanksin a little bit longer, and if the if the animal would have been euthanized, we'd see evidence of ulceration. Now, whether that was because of the flinixin or because of the disease process or a combination of both, it'd be hard to say. But when it comes to adverse effects, I typically think of flinixin as being uh more likely to cause them with a longer exposure, longer treatment duration than some of our other NSAPs. So after three days, I'm I'm normally reevaluating the patient. It's do I still feel they're hydrated? Do they still have a normal appetite? Do I see any evidence of teeth grinding, any altered urinary function, or any altered manure consistency? The one thing that's very frustrating for ruminants is that with abomace ulceration, we don't have an easy way to test for it.
Sarah:Right.
Joe:So my hospital population will do fecal-called blood testing to see, but in this is probably one of the only ways where I'm jealous of my eat fine colleagues, but if they think a horse has an ulcer, they can just fast it for a couple hours, scope it, and they get these really nice, you know, visual images of it. So I think it is worth being concerned here. For this study, we weren't looking at you know, fecal called blood after three days. You know, we were doing a physical assessment regularly, we didn't have evidence of teeth grinding. I know that if we had any alterations in their appetite or how much of the ration they were consuming, the husbandry staff at the goat facility, UC Davis, would have brought that to our attention. Um, the other thing to keep in mind though is that we did do this study in healthy goats. Right, right. One of the challenges for veterinary pharmacology is all of our studies are often done on healthy animals for drugs that were gonna determine how to apply in a sick animal. So I think that's something that whenever we use phonemixin for multiple administrations, it's worth keeping an eye on with respect to risk for ulceration.
Sarah:Good. Well, I'm glad I was I'm glad I'm doing that correctly. All right. Do you feel like we have touched everything on this great study that you would like the world to know about?
Joe:Yeah, there's a couple other things too, because we talked about like the plasma levels, and one part of the study was to evaluate two different diagnostic methods that were used for the sample. So mass spec, you know, versus Naliza. We didn't really find differences with the concentrations there on the same the same sample. So that might be that might be useful for future studies because if you use like a high pressure liquid chromatography, mass spectrometry, and you like that can be very economically challenging to do. Those samples are pretty expensive versus Naliza can simply typically be ran a little bit more um uh cheaper. Yeah. The other result that I just wanted to point out is we did take those, so we were collecting milk at these doughs too, and we were trying to, with the exception of the first hour, mimic the commercial milking schedule as much as we could, but we did use that information with both the FDA and the EMA, which is the European Medicines Agency, it's it's their equivalent when it comes to food safety. We used their methods to try to determine what a withdrawal would be. And because we don't have that tolerance, we just used the lowest, what's called the limit of detection. So it's the lowest uh amount that our assay could detect of five-hydroxy philinx and then the milk because we we can actually say zero because there's a after that lower limit of detection, you don't know if it's there lower, and we just kind of detect it or if it truly is zero. And with that, with those methods, we did find a withdrawal recommendation for milk that would be anywhere from like 36 to 60 hours. And I think the the EMA method is a little bit more conservative. And for the multiple dosing done subcutaneously, it was around 51 hours. So I think our recommendation was was 60. But I think it's also important to keep in mind like the total number of milkings there, too. Like it's never wrong to add you know another milking to one of these withdrawals if you're not sure.
Sarah:Absolutely, yeah. Just as an FYI, the current for the IV route is 36 hours for milk, and for the transdermal, it's 48. So that would be a little longer. What but we all know that if we give medicine extra label, sub Q, you need to, I don't know. To me, that's just like your vet should not should be saying if you give it as a different route, definitely extend it, you know, or call Farad and get, you know, for sure. I always add like multiple days. I mean, I really like to keep keep things clean as as much as possible.
Joe:Yeah, I'll do that myself too, because um, I'm always impressed with how quickly Farad gets responses back to us because it's like within one or two days now, it seems, but we're discharging a patient at the end and we need to you know give the client something. So sometimes I'll just make it really, really long if it doesn't matter, or sometimes I'll say pending. One thing I've seen with with Farad recently is for dairy animals, they'll recommend like so many negative tests. And I know on their on their website they have an increased like listing of all the stall side tests because we're just seeing more and more of those every year.
Sarah:Yeah. I guess I should I should explain a little bit for our our farmers out there. Farad is what it's an acronym for?
Joe:It's the Food Animal Residue Avoidance Data Bank.
Sarah:Okay, so they're basically an amazing resource, it doesn't cost us anything. We can reach out to Farad as vets and be like, you know, either I want to give this extra label or this was accidentally given extra label or something like that, and they will give us, they will get back to us, like you said, fairly quickly, what the meat and milk withhold should be for that, which is just so great, you know, because we work really hard to keep our food, our food clean. And so it's a really, really good resource that that vets use. So if you're a farmer or a producer and you're listening to this and you ever have a question, like you accidentally grabbed the wrong bottle and gave the wrong medication or gave it the wrong route, ask your vet. They can reach out to Farad and make sure that, you know, if you want to start drinking that milk or that animal is going to be slaughtered, you know, we can help you make sure that's safe. I mean, that's a great message for us to put out there because I would say most farmers and producers don't know that.
Joe:Yeah, and they're they're federally funded, but they I do not believe they have a regulatory component. And so if you if you have a question about a drug and and you gave something that maybe you realized after the fact, like I shouldn't have done this, and you reach out to them for advice and guidance, I don't think you have to worry about like the black helicopters coming down in your backyard shortly afterwards. Like it's just an advisory and education service, although they're doing a tremendous amount of research in this area too.
Sarah:Yeah, and we as vets don't even have to tell them who we're asking for, like we don't have to be like it was you know farmer X or Farmer Y. So yeah, I don't think people need to worry about that, but that's that's a great point.
Joe:Yeah, I felt like the first few times I used it, they thought I was using an alias because my name's so common, but I think they know it now. That's funny.
Sarah:Okay, so in our notes of the podcast, it'll have where you can find this paper. If you guys, I should say when you want to look it up yourself because you absolutely will want to. Dr. Smith, is there anything else you want to put out there about yourself? You know, do you have an amazing Instagram that you need people to follow or anything like that?
Joe:Uh I am on Instagram. It's at Joe Farmbet, and it's P-H-A-R-M.
Sarah:Clever.
Joe:But it it's I'm trying to get more of our work out there. We've done, you know, since the Flu Nixon study, one of the areas that we focused on as a group has been uh gastroprotectants in small roomness because we don't really have a lot of information, and up until a few years ago, everything we were using was based on an alpaca paper that was very well done, but it was it was done 10 years ago, and we're learning more and more that there's differences in those species versus goats. And we've also started to get involved with the some pain management, and so we have a couple studies going on there now where we're looking at now bufene in goats. It is an opioid, but it's not scheduled in most states, and so the thought there is maybe we'll have uh an analgesic that'll be more you know, more effective that could potentially be left on a farm because there's less abuse potential. So we're very early stages of that.
Sarah:Well, that's great. When that's done, give me a call and we'll talk about that. Put that out there for sure. All right, so I I assume you read in the script. I ask everybody our follow-up question. What do you see as the next problem that researchers need to think about and address in small ruminant medicine? In your field, outside of your field, shoot for the moon. There's no limitations here.
Joe:I I think it's a combination of two things. I think identifying more funding sources is unfortunately all these studies uh take resources. And I tell the students that, you know, well, you know, sheep and goats are major species. In my in my heart, I guess they're minor species, you know, from an economic standpoint, and it's challenging to find funding. But I think one of the ways that as a small ruminant community that we can overcome that is just more collaboration and collaborative studies. And I know there's been you know several studies recently that have been multi-center, um, but I also think there's potential for you know interaction in private practice and academics for some retrospective studies and trying to explore a couple of those right now. But I think the big needs are just finding more resources and then finding you know more creative ways to collaborate with each other. We all don't need to you know reinvent the wheel, we can work together for that.
Sarah:Yeah, and that's that's been the the response of multiple people that I've talked to. And ASRP, we are starting, we're we're trying our best to sponsor at least a study every couple years as we have funding for it. But yeah, it's it's rough in the small room in a world for sure. All right, do you anything else you want to throw out to our listeners, Dr. Smith, before we round it up today?
Joe:No, that's it. I'm very thankful for the opportunity. If anyone, you know, one of the things I enjoy doing is working with produ or excuse me, referring veterinarians that are trying to figure out drug solutions for their producers. And I'm happy to answer emails by that. And it's uh JSMIT604 at utk.edu. If anyone want to reach out. And again, thank you for the opportunity to talk about this project that you know I was part of the team that put together.
Sarah:Awesome. And that your email will also be in our our podcast notes so people can um look into that. Well, thank you very much. All right, just a little postscript at the end of this episode. Just once again, I like to drop a disclaimer here. Since this episode has covered topics pertaining to extra-label drug use, no part of this discussion today should be considered a treatment recommendation from me, Dr. Smith, or the American Association of Small Ruminant Practitioners. Banamine or flunixin is a prescription medication that requires veterinary oversight. So for producers, that means any and all questions about how to administer this drug should be directed to your veterinarian. For veterinarians, you should remember that the subcutaneous administration of banamine, although it's new and we're really excited about the work that Dr. Smith has done, it's still extra label. So when making treatment recommendations to clients, it is important to consider federal and all other laws and regulations regarding extra label drug use that apply to wherever you're practicing. Here in the United States, that should include a request to FARAD for withdrawal recommendations. All of this is to ensure that the food products from the animals that we treat are safe for human consumption. Thank you again for listening. If you have any questions, please feel free to reach out.
