A New Option For Chronic Arthritic Pain Management In Dogs – Galliprant

Ron Hines DVM PhD

 Arthritis In Your Dog

New Approaches To Arthritis & Pain Control In Dogs 

This article is about options available for your dog. Cats are known for not tolerating many medications that work well in dogs and humans – at least not at as high a dose. But when there is some information on how these drugs might perform in cats, I have included it here. Galliprant is not currently approved for use in cats.

If you follow the (ref) links in this article, the sensation of pain = nociception = nocioception = nociperception. I am sorry this article turned out so technical. If something is unclear; you can always ask me  to explain it.

Arthritis and joint pain are the most common disability affecting our pets as they age. But it can be hard for your veterinarian to confirm that your pet is actually suffering discomfort worthy of medications because, as in humans, the seriousness of the changes seen on x-rays don’t correlate well with the level of pain (if any) being experienced and many non-bone related problems associated with aging produce the same reluctance on a pet’s part to move about.

When joint pain and arthritis arrive sooner, it is often in the extra large breeds or in pets that are overweight or neutered too young – before their skeletal system had a chance to fully mature. (ref)

You many have gotten to this page from my Nexvet® link . That is another innovative pain-control option that might be released to veterinarians soon. But Galliprant is already available to your veterinarian. It was released to the US market for use in dogs in January of 2017. (ref)

Galliprant has been studied and developed under many names. They include AAT-007; CJ-023423; MR-10A7; RQ-00000007 and RQ-7.

The Story Of How Galliprant Was Discovered

Until 2007, Pfizer had a very productive drug discovery unit based in Nagoya, Japan. That same year, Pfizer announced that they intended to close that facility. Pfizer told the scientists that their choice was to seek transfer to another Pfizer location or seek other employment. But the scientific staff at the Nagoya lab was a tight-knit enthusiastic group. They held meeting and counter-proposed to Pfizer that the scientists keep the facility running themselves as an independent company. Pfizer, perhaps feeling guilty about their decision, contributed seed money, as did Japanese and UK venture capitalists. They named their new company RaQualia, a combination of the Egyptian sun god Ra and qualia or perception. (ref) As importantly, RaQualia was given the patents for 12 of the drugs they were developing – one of which was Galliprant. RaQualia limits its activities to proof-of-concept studies, then licenses the candidate drug patents to others. In the case of Galliprant (ref) , the patent was licensed to a veterinary drug startup, Aratana. Aratana has two veterinary drugs that are currently available. One, Entyce® , which has no current competitor, they market themselves. For the other, Galliprant, they teamed up with the veterinary division of a much larger drug company, Eli Lilly (Elanco), because there are a lot of competing anti-arthritis medications approved for dogs and introduction of another was going to be a marketing challenge. (Weintraub/fiercepharma2016) Eli Lilly had already invested heavily in research looking for similar drugs for humans. (ref)

How Is Galliprant Different From The Pain-Control Medications My Veterinarian Had Access To Until Now?

It revolves around prostaglandins and their roles in your pet’s body. Prostaglandins are messenger (signaling) compounds. When they are released within cells, they direct those, and adjacent cells to perform specific actions. Those actions include smooth muscle contraction or relaxation that affect blood flow, the birthing process, blood clotting, inflammation and pain. Some also influence the release of true hormones. In others situations, they encourage the production of a mucus layer to protect the pet’s stomach lining from corrosive stomach acids. Farther down the digestive tract, they help maintain a healthy intestinal lining. (ref) Prostaglandins are hormone-like. But true hormones move through the blood stream to the entire body after their release. The same prostaglandin can have different effects depending on the area of the body where it is released. Inflammation is a powerful stimulator of prostaglandin release. It’s release produces fever, summons cells of the immune system to the area and stimulates cells in that area to divide and heal. They also contribute to pain through direct stimulation of nerve endings in the area and the inflammation the compounds can generate.

All Non Steroidal Anti-Inflammatory Medications (NSAIDs) – the ones you take and the ones your pet takes – work by blocking the release of Prostaglandins. The early ones, like aspirin, indiscriminately blocked the production of two key enzymes necessary for prostaglandin formation (COX-1 & COX-2). Those earlier NSAIDs are non-selective – so they block the beneficial prostaglandin actions as well as the bad. Newer ones, home in more specifically on the COX-2 enzyme – the one responsible for forming the prostaglandins responsible for pain and inflammation. The Rimadyl®, carprofen, Novocox®, Carprieve®, Quellin®, Previcox®, Deramaxx®, Metacam®, meloxicam, Loxicom®, Orocam®, and Meloxidil® prescribed for dogs are all NSAIDs. Of them, Deramaxx® is probably the most COX-2 selective.

The only COX-2 selective NSAID left on the market for humans is Celebrex® . There were others – Vioxx® and Bextra® – but the FDA removed them due to safety concerns that emerged. (ref) Merck lost lost ~ $1.63 billion in the Vioxx debacle; Pfizer ~ $894 million in lawsuits over Bextra plus $2.3 billion in FDA fines for deceptive marketing. But the search for better ways to control arthritis pain goes on.

As time went by, scientists learned that prostaglandins required special receptors on cell surfaces in order for them to work. You might think of prostaglandins as keys that unlock start-and-stop processes within cells. When those locks or receptors are stimulated (unlocked) by a prostaglandin, the cell performs a certain action. Scientists also found that when prostaglandins unlocked (activated) of one particular cell receptor, EP4, it appeared to be most responsible for the pain and inflammation felt in that area. Scientists, including those at RaQualia, theorized that blocking the prostaglandin process farther “down stream” at the EP4 receptor might produce a pain and inflammation blocking drug with less side effects than the NSAIDs we currently use. (rptref1, ref2, ref3, ref4)

What Do The Galliprant Tests Show?

When it was still a division of Pfizer, RaQualia reported its earliest results with Galliprant in 2007. At that time, they called it CJ-023,423. (rptref) Five hours after receiving the compound, its effect on relieving foot pain in rats was slightly less than that of Feldene®, an old, non-selective NSAID that was given at the same dose. By 6.5 hours, the Galliprant effectiveness deficit was magnified (Fig7). But requiring a higher dose of a safer drug is not necessarily bad. There were other reports in the intervening years as attempts were made to interest major pharmaceutical companies in the drug. But it was not until 2014, after the compound had been sub-licensed to Aratana, that an article appeared on its possible use to relieve arthritis pain and inflammation in dogs. (ref)

In that 2014 study, the side effects Galliprant were explored in a small group of healthy beagle dogs for about a 9-month period. They did not say how old these beagles were (most researchers order beagles a bit less than 1 year old) but I assume that if they were elderly dogs or had concurrent health issues they would have said so. The dog’s general attitude and food consumption were noted every day and their weight measured weekly. Eye examinations, EKGs , clinical chemistry and urinalyses were conducted at intervals.

Aratana reported that there were no effects on the animal’s weight, food consumption, eye exams, EKG, blood values and blood coagulation. They saw no visual abnormalities in the body organs of the animals. They did report that at some of the doses used, signs of stomach and intestinal irritation (vomiting, diarrhea, blood in stool) did occur. Liver and kidney changes occurred in some of the dogs; they were not described but the Company considered them “minor”.

Their dose schedule ranged from 1 – 50 mg/kg/day (Galliprant ’s current suggested dose is 2 mg/kg/day) and they did not say at which dose(s) these “minor” changes occurred. This study is of little use in judging the long-term safety of Galliprant. It does not examine the effectiveness of the medication in blocking pain or inflammation or what it might do in the ‘at risk” elderly dog population that is most likely to receive the product.

In 2014, Aratana also presented some data to the Securities & Exchange Commission (SEC). It reported on a study they had performed that compared the stomach safety of Galliprant to an old, never-approved-for-dogs NSAID, naproxen ; and suggested that the results suggested that Galliprant was safer than other NSAIDs. I have problems with that. But you will have to read it and make your own decisions. (ref) You can read about naproxen and what it can do to dog here.

In 2016, Aratana published a review article to introduce the veterinary community to Galliprant. (ref) It suggested that Galliprant, could be more selective in relieving joint pain and inflammation because it focused on the E4 receptor I mentioned earlier. That might result in less stomach/intestinal upsets and, perhaps, other unwanted side effects . It mentioned that dogs do not seem to be susceptible to the heart complications that drove earlier COX-2 blockers like Vioxx and Bextra from the market (One of God’s blessings to our pets is that dogs and cats just don’t get the heart attacks and coronaries that we humans do). But dogs do occasionally develop stomach/intestinal, liver or kidney problems on dog-approved NSAIDs (ref1, ref2, ref3) That list, maintained by the FDA, now includes Galliprant. (ref) There have been a few more publications. But they do not tell us much more about how Galliprant will perform. (ref1, ref2)

You see, practicing veterinarians like myself can’t judge the effectiveness or desirability of one medication in a group over another without comparing the drug’s effectiveness and safety to other medications in the group when neither the vet or the owner knows which is which (a double blinded study) – and none of the Galliprant studies do that. Pain intensity is one of the hardest things for researchers in medicine to measure. That is because pain is a highly subjective thing in humans. In people, placebos always have a more positive effects against pain than researchers wish for. That’s why the airways are full of products – from copper bracelets (ref) to healing pyramids. But that is not to say that placebos are fake or dishonest – they truly do lessen pain – if you believe in them. Above all, your dog’s mood keys off of your mood. So, perhaps, some of that healing optimism and hope even rubs off on them. (ref) I can not say.

That same effect makes pet-owner questionnaires just as unreliable when it comes to judging the effectiveness of pain control medications in our dogs and cats. We love our pets and dearly want those medications to work. Perhaps the only way around that is to use activity monitors (3-axis accelerometers) (ref1 ref2 ref3), in one group of pets that receive a medication and another group who receive another medication or none at all. None of the Galliprant or Nexvet® studies did that.

Were Any Tests Run In Cats?

Just one published study that I am aware of. (ref)

However, in 2014, Aratana submitted a document to the US Securities & Exchange Commission regarding pilot studies on the use of Galliprant (=AT-001) in cats. That submission appeared to indicate they had faced liver issues in some of the cats and were working to see if a way could be found around that. (ref) Cats are thought to be more susceptible to NSAID side effects than dogs or humans. (ref1, ref2)

My Joints Are A Little Achy Too, Why Aren’t Drugs Like Galliprant Approved For Human Use?

I was curious about that too. So I asked the head of the Department of Systems Pharmacology and Translational Therapeutics at the School of Medicine, University of Pennsylvania that question. He answered: “I think the whole Vioxx experience has stilled the ardor of industry for any drug development in this pathway, no matter how illogical that may seem”.

I told you about the Vioxx/Bextra experience earlier. COX-2 specific NSAID research and development has been a double-edged sword. (rptref) The financial rewards to pharmaceutical companies for success are tremendous – but the punishment for failures is just as severe.

RaQualia, the owner of the Galliprant patent, had an agreements with a Japanese pharmaceutical company (Maruishi Pharma Co Ltd) and Chiba University to develop human uses for Galliprant (aka RQ-00000007). I believe those projects are now inactive. As late as mid 2016, they were still tinkering with the Galliprant molecule in an attempt to improve its “efficacy [and] safety”. (ref) They did obtain a Japanese use patent in 2017 (No. 2012-538520) to explore the drug’s effectiveness as a treatment for autoimmune disease (E4 (=EP4) inhibitors have inhibitory effects on some immune system cells as well [ref]) and one in the US to explore its use in the treatment of cancer (No. 14/547,247).

Eli Lilly (the owner of Elanco, the Galliprant marketer) was said to be in early development of a NSAID E4 antagonist in 2014 (Galliprant is also an E4 antagonist). (ref1, ref2) As recently as February, 2017, they were still looking at the effects of several anti-E4 compounds (including Galliprant = CJ-023,423) but had gotten no further than giving them to rats. (ref1, ref2)

Drug companies are often reticent (hesitant) about reveling what they are up to. Competition between them is intense in the crowded field of pain control medications. What is clear is that they are still uncertain as to what all the actions of prostaglandins are and the ramifications (consequences) of blocking them. Some companies, like Lilly and RaQualia concentrate on blocking the EP4 receptor with medications like Galliprant. But others, like Allergan, feel that multiple receptors, not just EP4, need to be targeted for maximum relief of pain and inflammation. (ref)

Do You Think That Galliprant Is Better For My Dog Than The Medications That My Vet Has Had On The Shelf Until Now?

If your dog does not handle deracoxib (Deramaxx®), carprofen (Rimadyl®, Novocox®, Carprieve®, Quellin®, Carprofen), meloxicam (Metacam®, Loxicom®, Orocam®, Meloxidyl, Meloxicam) or firocoxib (Previcox®) well, an alternative like Galliprant or perhaps Nexvet® ‘s  when it is approved, might be a better option. No one really knows. It is new on the market and, as I mentioned, no tests that I know of show that it is equal or superior to the older medications in preventing unwanted side effects or in its pain-relieving qualities. Side effects from the dog-approved NSAIDs are not that common in dogs when they are given correctly. (ref) How the long-term use of those products might affect a dog’s kidneys or liver remain unknown for all of them.

    Read or add pet owner feedback  here 

With time and feedback from pet owners, the value of this new medication will become more apparent. If you used another medication before and now give your dog Galliprant, I would appreciate your feedback and I will post it at the bottom of this article. Let me know:

1) How old is your dog and what is its breed and sex ?
2) Was Galliprant as effective or more effective in allowing your dog to move about better ?
3) Were there less side effects than with its prior medication ?
4) Were there good or bad changes in its blood work results in contrast to its prior medications or no changes at all ?
5) If you use an activity monitor on your dog present those important results as well.

Are There Precautions I Should Take While My Pet Is Taking Galliprant?

Never give an arthritis/pain control medication at higher than the suggested dose. Never give more than one form of arthritis/pain control medication at one time – without the knowledge of your veterinarian. (ref)

Mother Nature never develops or perpetuates a complex signaling system like prostaglandins with out a good reason. Such systems are complex and not fully understood. They have multiple functions with good as well as bad consequences and the results of suppressing or stimulating them vary depending on the place in the body where its influence occurs (it varies from tissue to tissue). I would suggest that dogs on Galliprant – or any NSAID long term – have periodic blood chemistry and CBC counts. The tests that monitor liver and kidney health would be of most interest to me – as would evidence of anemia, blood protein  deficiencies or changes in its WBC count. A baseline test, performed before beginning these medications, would be highly desirable as well. You can read about the complexity of the EP4 receptor system here  and here (antagonists like AE3-208 decrease EP4 actions, agonists like AE1-32 increase them).

Any change in your pet’s body weight, appetite, stool consistency or your pet’s general attitude ought to be brought to the attention of your veterinarian.

I would stop giving all NSAID medications during periods of infectious illness of any kind since EP4 blocker are known to inhibit certain cells of the immune system (Th1 cells ). We really understand very little about what the consequences of blocking the beneficial effects of prostaglandin (PGE2/E2) might be. (ref1,ref2,ref3)

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