September 14, 2017

Non-COX Inhibitory Drugs to Treat OA in Companion Animals

Panelists B. Duncan X. Lascelles, BVSc, PhD, DACVS; Sheilah Robertson, BVMS, PhD, DACVAA, DACAW, DECAW; Margaret Gruen, DVM, MVPH, PhD, DACVB; and Mark Epstein, DVM, DABVP, CVPP, share their views about different non-COX inhibitory drugs for the treatment of osteoarthritis in companion animals.

B. Duncan X. Lascelles, BVSc, PhD, DACVS: Let’s move on in that direction. I think we all agree that nonsteroidals are effective analgesics and that they will help prevent musculoskeletal system deterioration, somatosensory system deterioration, as well as have effects on the sensitization—wind-up—and can prevent a decline in cognitive function and those other deleterious effects on sequalae. In still trying to think about effective analgesics, outside of COX (cyclo-oxygenase-2) inhibition, Sheilah, what options do we have?

Sheilah Robertson, BVMS, PhD, DACVAA, DACAW: If we’re focusing on drugs, it has been mentioned, briefly, that we’ve got the piprants. What we’re trying to do is go for targeted therapy. In the past, we’ve blocked pathways that lead to what we don’t want. So, if you think about it, way back we had corticosteroids. Then, we got a little bit lower down the pathway, and we got individualized COX1 and COX2 inhibitors. And now, what we’re trying to do is get lower down the pathway. So, for example, the piprants.

B. Duncan X. Lascelles, BVSc, PhD, DACVS: Which is this drug that we’re talking about?

Sheilah Robertson, BVMS, PhD, DACVAA, DACAW: The drug would be grapiprant, which is approved for dogs. We already have that drug. It’s working as a receptor blocker, so we’re looking at blocking receptors rather than inhibiting a pathway, which might have actual beneficial effects in some ways. I think going for the targeted therapies is definitely important in these animals, especially ones with comorbidities where we’re less likely to have complications if we go for targeted treatment. So, I think having the piprants—especially grapiprant, which we now have for dogs and, hopefully, we might see it for cats—is big. That would be the one thing. There has been very little attention paid to the lipoxygenase pathway for a long time, which we know is involved. But it has not been talked about for a long time. We’ve only ever had 1 dual inhibitor on the market, and it’s no longer available.

B. Duncan X. Lascelles, BVSc, PhD, DACVS: That’s a great non-COX inhibiting option—grapiprant, the first of the piprant class. Margaret, we talked earlier about nerve growth factor and preventing its action. Is that going to be an effective analgesic in the same degree as the nonsteroidals or maybe greater?

Margaret Gruen, DVM, MVPH, PhD, DACVB: It appears to be. What we saw in cats is that the improvement on an activity monitor basis is the same or more than a nonsteroidal. And the benefit, particularly for cats, but even for dogs, is that it’s an injection that’s given over spaced intervals. So, for cats that are difficult to give a medication to every day, it’s a potentially very attractive owner option. And it’s attractive for the cats. So, I think that that monoclonal group is going to be really interesting and effective.

B. Duncan X. Lascelles, BVSc, PhD, DACVS: So, not quite with us yet?

Margaret Gruen, DVM, MVPH, PhD, DACVB: Not quite with us yet, but very close.

B. Duncan X. Lascelles, BVSc, PhD, DACVS: Very close. On that note, what other potential therapies, non-COX inhibiting therapies, are on the horizon, sticking around this theme of really effective, predictable pain relief?

Mark Epstein, DVM, DABVP, CVPP: There are other pathways off that arachidonic acid pathway that are under investigation, right now. Soluble epoxide hydrolase inhibitors—I won’t go into the neuropharmacology of that, but it can potentially give anti-inflammatory analgesic effects with possibly a little better adverse effect profile than the COX inhibitors.

B. Duncan X. Lascelles, BVSc, PhD, DACVS: These are drugs that increase the production of anti-inflammatory…

Mark Epstein, DVM, DABVP, CVPP: Correct. At the end of that pathway are pro-inflammatory molecules. If you inhibit that, they shunt over to these anti-inflammatory molecules. So, that is the crux of it. Like I said, they’re just investigational right, now but there’s promise. We have, of course, the whole realm of the SNRIs that we use a lot. We use these products. Gabapentin we use a lot, but we just don’t have a lot of data about it. Amantadine is your study. So, we use them, but we just don’t have a lot of data about them, and I think that those are areas that deal with maybe treating or preventing some of the damage to the spinal cord—the sensitization component. So, those will be critical.

One area that we really haven’t talked too much about, here, are other biologics. These are intra-articular injections, and these may be as infrequent as every 6 months or a year. Who knows. We don’t. This is where we have the promise of stem cells. It’s moving from the autologous mesenchymal. The research is now over to the allogeneic, universal donor type and then PRP plus or minus hyaluronic acid. So, we’re in the Wild West of those, I have to say. We do utilize them in our practice, and there’s evidence that is encouraging. It’s all pointing to a clinical benefit, but we really don’t know the highest, best, wisest, and safest uses of those products, and they are minimally invasive. You do have to be able to get into a joint. The hip is not as easy as others, as Bryan would say. And yet, they show, in my view, pretty nice promise.

B. Duncan X. Lascelles, BVSc, PhD, DACVS: So, we have the nonsteroidals that are predictably efficacious analgesics. We have the piprants. And right on the horizon, we have the anti–nerve growth factor therapies that look extremely promising in terms of pain relief. And there are a number of other possibilities coming down the line.

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