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

 = Grapiprant

Ron Hines DVM PhD

 Arthritis In Your Dog

Other Approaches To Arthritis & Pain In Dogs  

This article is about medication options that are available for your dog. Cats are notorious for not tolerating many medications that work well in dogs and us humans – at least not when given in as high a per weight dose. But if there is information on how these medications perform in cats, I included them in this article. Galliprant® is not currently approved for use in cats.

When I originally wrote this article all published scientific studies of Galliprant®/grapiprant originated with the manufacturer of the time, Aratana or its predecessor, Pfizer. Since then, two additional studies appeared in the literature. The first compared the effectiveness of Galliprant® to that of firocoxib/Previcox®. Read that one here. The conclusion of the authors was that Previcox® was superior to Galliprant®. Since it was paid for by the makers of Previcox®, one might question its validity. However shortly thereafter a second study appeared that compared Galliprant® to carprofen/Rimadyl®. It was a well-designed crossover study and it also found little benefit attributable to Galliprant®. Read that one here. That study had no outside funding.

If you search online, the sensation of pain = nociception = nocioception = nociperception. 

As your dog gets on in years, it will glow silver around its muzzle and its paws. Its vision and hearing will probably decline and it will usually sleep more. Your dog’s mental abilities and success at surmounting new challenges might not be as good as they once were. Arthritis and joint pain are not inevitable, but they are common canine age-associated events. That doesn’t mean that your dog is unhappy – dogs do not dwell on their disabilities. It can be hard for your veterinarian to confirm that your pet is actually suffering bone and joint discomfort worthy of medications. That is because like in humans, the seriousness of the changes that your veterinarian sees on your pet’s x-rays don’t correlate well with the level of pain (if any) being experienced.  And many of the non-bone or joint related problems of older dogs produce the same reluctance on their part to move about. When joint pain and arthritis arrive earlier in life, it is often in the extra large breeds, pets that are overweight or that were neutered at too young an age – before their skeleton and ligaments had a chance to fully mature. ( read here & here ) Genetically dysplastic breeds are also at higher risk. (read here)

You many have gotten to this page from my Nexvet® article link . That is another innovative pain-control medication that Zoetis plans to release to veterinarians soon. But Elanco’s Galliprant® ( grapiprant ) is already available through your veterinarian. It was FDA approved for use in dogs in 2017. Over the years, the Galliprant®/grapiprant compound has had studies reported under various names. They included 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. As importantly, RaQualia was given the patents for 12 of the drugs Pfizer was developing in Japan. One was Galliprant®. RaQualia limited its activities to proof-of-concept studies and then licensed the candidate drug patents to other pharmaceutical companies to actually produce. In the case of Galliprant®, the patent was licensed to a United States veterinary drug startup, Aratana. Aratana has two veterinary drugs currently available. One, Entyce® , which has no current competitor, they marketed 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. They knew that introducing another was going to be a marketing challenge. Eli Lilly had already invested heavily in research looking for similar drugs for humans. ( read here ) In 2019, Elanco went ahead and purchased the entire Aratana company. 

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. ( read here ) 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 simulator 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 actions of beneficial prostaglandin as well as the bad ones. The newer NSAIDs 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 the newer type of NSAID. Of them, Next to Galliprant®, 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 from the market due to safety concerns that emerged. ( read here ) 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. 

What Do The Galliprant Tests Show?

When it was still a division of Pfizer, RaQualia reported its earliest results with Galliprant. At that time, they called it CJ-023,423. 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 even larger. But requiring a higher dose of a safer drug is not necessarily bad thing. 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. read hereIn that 2014 study, the side effects of 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. Aratana also presented some data to the 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 data. But you will have to read it and make your own decisions. read here 

In 2015, Aratana published a review article to introduce the veterinary community to Galliprant®. ( read here ) It suggested that Galliprant®, could be more selective in relieving joint pain and inflammation because it focused on disabling the EP4 pro-inflammatory 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 don’t suffer the heart attacks and coronary artery disease that we do). But dogs do occasionally develop stomach/intestinal, liver or kidney problems when given dog-approved NSAIDs. ( read here,here & here) That list, maintained by the FDA, now includes Galliprant®. The few studies that have been published since 2016 did not rate the effectiveness of grapiprant/Galliprant high. (read here&here)

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 veterinarians administrating it or the dog owners knows which is which (=a double blinded study) – and none of the Galliprant® studies did that. Pain intensity is one of the hardest things for researchers in all branches of medicine to measure. That is because pain is a highly subjective sensation. In people, placebos always have a more positive effects against pain than scientists wish for. That is the magical effect of optimism and hope. It is why the airwaves are full of products – from copper bracelets ( read here ) to healing pyramids But that is not to say that placebos are fake or dishonest – they truly do lessen our pain – if  you believe in them. And above all, your dog’s mood keys off of your mood. So, perhaps, some of that healing optimism and hope rubs off on them. read here I cannot say. That same phenomenon (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 so much and we dearly want those medications to work. I believe that the only way around that is to use activity monitors (3-axis accelerometers). ( read here, here & here ) Veterinary pharmaceutical companies are always reluctant to do that when it comes to comparing the effectiveness of their products those of their competitors.

 

Were Any Tests Run In Cats?

Just one published study that I am aware of. ( read here However Aratana submitted a document to the US Securities & Exchange Commission regarding pilot studies on the use of Galliprant® (=AT-001) in cats. That submission indicated that some of the cats given Galliprant® developed liver issues when given the drug and that they were looking for a way around that. read here Cats are considerably more susceptible to NSAID side effects than dogs or humans. 

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. The financial rewards to pharmaceutical companies for success are tremendous – but the punishment for failures is just as severe. RaQualia, the former owner of the Galliprant® patent, had an agreements with a Japanese pharmaceutical company and Chiba University to develop human uses for Galliprant® (aka RQ-00000007). Those projects were discontinued. As late as mid 2016, they were still tinkering with the Galliprant molecule in an attempt to improve its “efficacy and safety”. Eli Lilly, the parent company of Elanco, was said to be in early development of a NSAID E4 antagonist (Galliprant® is also an E4 antagonist). 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.  Some companies, like Lilly concentrate on blocking the EP4 receptor with medications like Galliprant®. But others, like Allergan, feel that multiple receptors, not just EP4, need to be blocked for maximum relief of pain and inflammation. 

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® and perhaps Nexvet® ‘s  when it is approved, might be worth a try. Every dogs is unique, but I do not know of any veterinary pharmaceutical company that has proven that their product is any more effective than the others.  Side effects from the FDA dog-approved NSAIDs are not that common when they are given to your pet in the correct dose. (read here) However how the long-term use of all these products might affect your dog’s general health remain unknown.

Read or add pet owner feedback On Galliprant® here  

With time and feedback from pet owners like you, the value of this medication will become more apparent. If you used another medication before for your dog’s arthritis and then gave it Galliprant® or vice versa, I would appreciate your observations and will post it through the feather link above.

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 or pain control medication at one time – without the knowledge of your veterinarian. ( read here )

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 given 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 any 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. 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. 

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