Currently, many of the laminitic horses I see as a farrier have been diagnosed by a veterinarian as having PPID (pituitary pars intermedia dysfunction), EMS (equine metabolic syndrome), IR (insulin resistance) and/or obesity issues.
In many of these cases, the veterinarian has prescribed phenylbutazone (PBZ) or bute for various reasons. I have also witnessed horse owners judiciously giving bute on their own to help with pain relief for their horse. It is not uncommon to hear that many of these horses are on 4 to 8 grams of veterinarian-prescribed or owner-given bute a day for weeks on end.
Over the past few years, I have seen several horses on high doses of bute die from renal (kidney) failure. One of my mentors, International Equine Veterinarian Hall of Fame member George Platt, used to talk about getting horses off bute as it masks pain and because he found that horses recovered quicker when not on bute.1,2,3,4,5 My own personal experiences seem to validate his comments in general, although I have seen horses on low dosages of bute recover without any issues.
Therefore, I took to the telephone, library and Internet to do a little more investigating on the use of bute. My goal was to learn more about this commonly used drug. As I began my investigation, I focused more on the use of bute with EMS, IR and PPID laminitic/foundered horses.
The first area I focused on was the possible toxicity issues with bute. I found that an overdose with bute can occur relatively easily if recommended medical doses are exceeded.6,7,8,9,10 One of the most common issues that many people are aware of are the gastrointestinal issues from long term or higher doses of bute.6,8,11,12
Bute is also the most toxic of the NSAID's (non-steroidal anti-inglammatory drugs).9 Looking into bute toxicity concerns relevant to the laminitic horses I work on, the toxic effects of bute are related to the horses that receive more than 0.4 grams/100 pounds of body weight per day for 4 days (4 grams to a 1,000-pound horse).13,15 Research also suggests that higher doses of bute are not associated with greater analgesic effects.14
One U.S. study found that horses receiving the maximum 4 grams/day oral regime for only 4 days began to lose their appetite, become depressed and develop intestinal and kidney problems. The drug appears to decrease the flow of blood to the kidneys, causing retention of water and sodium, which poses added risks for horses with a congestive heart condition.16
The conclusion on the risk of toxicity is clear — the research validates that no horse should exceed the 0.4 grams/100 pounds of body weight per day for 4 days.
As a farrier then, what should I do when I walk into these situations where horses are being given 4 to 8 grams/day of bute? If the horse owner is administrating the bute, it would be advisable to inform the owner that they shouldn't be administrating bute without veterinarian approval and dosage recommendations. But what if the veterinarian prescribed toxic levels of bute? I can tell you from personal experience that private conversations expressing concern for the high level of bute do not go over well.
Pain Relief Vs. Pain Reduction
The question is why are the majority of laminitic horses I'm called in to provide farrier treatment for on such high doses of bute? The answer is rhetorical as it's fairly obvious the reason is to provide some pain relief for these often excruciatingly painful or possibly recumbent horses.
There is some humane justification for the judicious use of pain relievers, but one should be aware of the downsides.17 Pain relief might increase mobility that exacerbates tearing of the laminae.17 It does not prevent or stop laminitis and has been shown to alter the course of acute cases.17
Pain has a very important protective effect. The administration of bute during the developmental and acute stages of laminits reduce foot pain and create a more comfortable looking horse, but the disease is still a concern.17?This creates an ethical dilemma, balancing the need to alleviate pain and suffering against the realization that most of what is administered is no dealing with the underlying cause.17, 18 We want to target the excruciating, excessive pain that is so crippling to the horse. What we strive for is pain management, not elimination. We want to leave just enough protective pain, but lessen some of the laminitic pain.19
The indiscriminate use of bute often interferes with my ability to accurately evaluate the horses current condition, provide an accurate mechanical treatment evaluation and sometimes interferes with the monitoring of the horses progress. I have also witnessed horses whose pain has been so masked that they continued to further damage their feet with stall walking, decreasing foot pumping and weight shifting or kept them on their feet instead of possibly laying down to rest.
As a farrier dealing with many laminitic/foundered horses, I personally look forward to the results of the clinical trials being done by University of California - Davis on the EH inhibitors.19 This could be the answer we have been searching many years for, a pharmaceutical drug that can safely provide pain management and not pain elimination.19
The conclusion on pain relief is, I think, any pain masking drugs should be used carefully and judiciously. I also believe there needs to be some serious horse owner education on the indiscriminate use of bute without a veterinarian's consultation, as well as more discriminate use of the drug by veterinarians.
Thyroid Level Reduction
The next issue I looked at dealt with bute’s effect at lowering thyroid blood levels, causing false low results by significantly decreasing T4 (thyroxine) and fT4 (free thyroxine) concentrations.20 Phenylbutazone also has been shown to interfere with thyroid-function tests by competing with thyroxine at protein-binding sites or by inhibiting thyroid-iodine uptake.21,22
Most people are not aware that bute might be lowering their horse’s thyroid levels.23 In a 2006 proceedings paper for the AAEP, equine vet Nicholas Frank wrote that scientists have come to realize that low thyroid levels were a consequence rather than a cause of the horse’s metabolic issues and may even be the result of the use of phenylbutazone.23,24
To deal with this issue, thyroid hormone supplementations such as levothyroxine are used. Frank feels thyroid supplementation does have some pharmacologic effect on horses, and his research shows the use of levothyroxine induces weight loss and increases insulin sensitivity.23,24,25 However, to be effective, bute must be eliminated in order for levothyroxine to be a benefit. Unfortunately, this is not the case in many laminitic horses I provide farrier treatment for.
The conclusion on thyroid level reduction shows that bute clearly affects thyroid levels in horses. This especially would be of concern with laminitic IR, EMS and PPID horses. Thyroid supplementations have been shown to help with the increasing of thyroid levels in horse's. However, bute should be eliminated during this process. Therefore, it seems like another pain relieving drug other then bute would be warranted if the horse needs thyroid hormone supplementation.
The next issue I found was with bute inhibiting bone healing. Dealing with chronic laminitic horses with bone degeneration can be a frustrating part of veterinarian and farrier treatment due to the constant pain many of these horses are experiencing. There are several medical and mechanical treatment options that can be provided. During my research, I found an issue with bute being utilized in these cases.
Drugs that help control pain, NSAIDs like bute, inhibit bone healing.26 Data on bone healing and NSAID administration primarily has been generated from rodents and rats.26 Nonetheless, this point seems clear: when given at high doses and for long durations, NSAIDs negatively impact bone healing.26,27 The bone healing rate in horses is decreased with the use of bute.28 Whether the effects of NSAIDs on bone healing are clinically important or not remains controversial.29,30
The conclusion on inhibiting bone healing is clear that more research is warranted, but there seems to be merit that bute should not be administered in chronic laminitic horses where bone healing is desired. This is another reason why EH inhibitors may be desired.
Not Good For Humans
Due to phenylbutazone's serious adverse effects, further investigations culminated in its unavailability for human use in the U.S. While phenylbutazone became available for use in humans for treatment of gout and rheumatoid arthritis in 1949, it is not approved or marketed for any human use in the U.S.31 Bute is known to induce blood disorders such as aplastic anemia,32,33,34 agranulocytosis, hypoglycemia (low glucose levels)34,35,36 and several other life-threatening illnesses.29,34,36
In humans, bute causes decreases in blood glucose levels and fasting hypoglycemia.29,34,39,36,40,41
Phenylbutazone is a widely used pharmaceutical in the equine industry due to its availability and relatively inexpensive cost. Bute is approved for oral and injectable use in dogs and horses, but is not approved for any food producing animal and its labeled use in horses is strictly limited to horses not intended for food.31,37,38
In animals, bute utilizes high potent direct compression sweeteners in the flavoring agent in order for it to be more palatable.42,43,44 Sweeteners used in the flavoring agent may be any type of compatible sweetener, either from a natural material or an artificially produced sweetener.42,43,44
Artificial sweeteners such as saccharine, acesulfame potassium and aspartame are preferred for cost reasons, and unlike natural sugars, they do not promote significant tooth decay (shown in humans).45 Examples of natural sweeteners are sucrose, glucose, fructose, lactose, acesulfame-K, dextrose, and sucralose. Xylitol, a common artificial sweetener, lowers blood sugar dangerously in dogs and sometimes humans.46
The answer on bute decreasing blood glucose levels has been demonstrated in humans. What about in horses and what would be the consequences of that with IR, EMS and PPID horses?
Insulin levels in IR and EMS horses are elevated and usually glucose levels are near normal levels. If bute creates hypoglycemic response (lowering glucose levels), this could be problematic for the IR and EMS horse.
Research has shown that sugar ingestion in horses causes increases in insulin levels. Looking into bute's high potency sweeteners and binders, I'm not aware nor could I find any research on their effect on horses. Canine research showed one tested sweetener dangerously lowered blood sugar. Therefore, until this answer is found, continued monitoring of blood glucose levels by the veterinarian would be warranted. If hypoglycemia is found, bute should be eliminated.
In conclusion, I think there are several considerations of bute use in IR, EMS and PPID laminitic horses.
- The first is owner compliance and education on bute usage.
- The second is limiting the amount of bute given so as not to create toxicity issues.
- The third is to use bute carefully and judiciously and limit the indiscriminate use of bute for pain masking.
- The fourth is since bute clearly lowers thyroid levels, the horse should receive thyroid hormone supplementation.
- The fifth is that another pain-relieving drug may be warranted in chronic laminitic horses because bute inhibits bone healing.
- The sixth is that blood glucose levels should be tested in IR, EMS and PPID horses and bute discontinued if it causes hypoglycemia.
1 - Laminitis. Platt, G and Chapman B. Proceedings of the Thirteenth Annual Am Assoc Equine Pract Convention, Dallas, Texas, December 1984.
2 - Laminits and Hear Bar Shoes. Burney Chapman and George W. Platt, DVM. American Farriers Journal, May/June, 2000, pp 70-1.
3 - Principles of Laminitis/Founder Treatment. Geogre Platt, DVM. Farrier Focus Study Guide, November 10-11, 2000, p 22.
4 - Platt, DVM, George, (Personal Conversations) 1999, 2000, 2002.
5 - Drugs Vs. Heart Bars For Treating Founder. George Platt, DVM. American Farriers Journal, March/April 2001, p 64-7.
6 - The Use of Phenylbutazone (bute) in Horses. Stablemade.com, 2009, p 2-3.
7 - Myths and truths about controlling pain and inflammation in horses. March 13, 2002. http://www1.agric.gov.ab.ca/$department/deptdocs.nsf/all/hrs3708.
8 - Effects of Top-Dress Formulations of Suxibuzone and Phenylbutazone on Development of Gastric Ulcers in Horses. Andrews FM, Reinemeyer CR, and Longhofer SL. Vet Therap. Vol 10, No 3, Fall 2009.
9 - Analgesia and Anaesthesia. MA Healthcare, LTD. Equine Health, Sept/Oct 2015.
10 - Bute: How Much is Too Much. King M. The Horse. http://www.thehorse.com/articles/15770/bute-how-much-is-too-much.
11 - Phenylbutazone toxicosis in equidae: a biochemical and pathophysiological study. Snow, DH, Douglas TA, Thompson H, Parkins JJ and Holmes PH. Am J Vet Res. 1981 Oct;42 (10):1754-9.
12 - Effects of toxic doses of phenylbutazone in ponies. MacAllister CG. Am J Vet Res. 1983 Dec;44(12):2277-9.
13 - Phenylbutazone toxicosis in the horse: a clinical study. LG Collins and DE Tyler. J Am Vet Med Assoc. 1984 March 15;184(6):699-703.
14 - Evaluation of the analgesic effects of phenylbutazone administered at high or low dosages in horses with chronic lameness. Hu HH, MacAllister CG, Payton ME, Erkert RS. J Am Vet Med Assoc, 2005 Feb; 1:226(3)414-7.
15 - Review: The use of phenylbutazone in the horse. Soma LR, Uboh CE and Maylin GM. J Vet Pharmacol Therap. 2011 June; 35, 1-12.
16 - Bute and horses: care is needed. Neil Clarkson. horsetalk.co.nz. December 5, 2012.
17 - Acute Laminitis: Are Drugs Effective? Annual Am Assoc Equine Pract Convention, San Diego, California, 2008.
18 - Laminitis: What Treatment at What Stage? Christopher C. Pollitt, BVSc, PhD. 10th Geneva Congress of Equine Medicine and Surgery. Geneva, Switzerland, December 11- 13, 2007.
19 - Research Continues on Drug That Treats Laminitis Pain. Tearney, P. American Farriers Journal. March 2015, p 64-69.
20 - Serum triiodothyronine, total thyroxine, and free thyroxine concentrations in horses. Sojka JE, Johnson MA and Bottoms GD. Am J Vet Res. 1993 Jan;54(1):52-5.
21 - Duration of effects of phenylbutazone on serum total thyroxine and free thyroxine concentrations in horses. Ramirez S, Wolfsheimer KJ, Moore RM, Mora F, Bueno AC, Mirza T. J Vet Intern Med. 1997 Nov- Dec;11(6):371-4.
22 - Measurement of free thyroxine concentration in horses by equilibrium dialysis. Breuhaus BA, Refsal KR, and Beyerlein SL. J Vet Intern Med 2006;20:371-376.
23 - Insulin resistance in horses. Frank N. Annual Am Assoc Equine Prac. Vol. 52, 2006, pp 51-54.
24 - Equine Metabolic Syndrome. Frank N, Geor RJ, Bailey SR, Durham AE, and Johnson PJ. J Vet Intern Med 2010;24:467-475.
25 - The myth of equine hypothyroidism. Kenneth Marcella, DVM. DVM360 Magazine, November 1, 2011.
26 - Researcher: NSAIDs Help Pain But Not Bone Healing. Stacey Oke, DVM, MSc. The Horse.com. November 24, 2010, article 17290.
27 - Non-steroidal anti-inflammatory drugs inhibit bone healing: a review. Barry S. Vet Comp Orthop Traumatol. 2010;23(6):385-92.
28 - Effects of phenylbutazone on bone activity and formations in horses. Rohde C, Anderson DE, Bertone AL, and Weisbrode SE. Am J Vet Res. 2000 May;61(5):537-43.
29 - Final Diagnosis - Phenylbutazone Toxicity. Case 268. path.upmc.edu/cases/case268.
30 - Phenylbutazone in the Horse: A Review. Tobin et al. J Vet Pharmacol Therap. 1986:9:1-25.
31 - Association of phenylbutazone usage with horses bought for slaughter. Dodman N, Blondeau N and Marini A. Food & Chem Tox. 2010;48:1270- 1274.
32 - Aplastic anemia from veterinary phenybutazone. Ramsey R and Golde DW. JAMA. 1976;236:1049.
33 - Misuse of veterinary phenylbutazone. Carpenter SL and McDonnell WM. Arch Intern Med. 1995 June 12;155(11):1229-31.
34 - Phenylbutazone. National Library of Medicine HSDB Database.
35 - Hypoglycemic Disorders. Amir Hanna. Endocrinology Rounds. December 2003, Volume 3, Issue 10. endocrinologyrounds.ca.
36 - Hypoglycemic Drug Interactions. October 2001. sdh.sk.ca/RxFiles.
37 - Phenylbutazone Veterinary Systemic. The United States Pharmacopeial Convention, 2004.
38 - Extra label Use of Phenylbutazone banned in Dairy Cattle, JAVNA News, April 15, 2003.
39 - Nutrient Drug Interactions. The Merck Manual Professional Edition.
40 - Diseases, Medical Conditions and Deficiencies that are Associated with Blood Sugar and Insulin Control, http://www.webshopemporium.com/BloodSugarControlRelatedDiseasesDefi ciencies.htm.
41 - Drug-Induced Disorders of Glucose Tolerance, Manjula K. Pandit, MD; John Burke, RPh, MA; Anthony B. Gustafson, MD; Anil Minocha, MD; and Alan N. Peiris, MD, Ann Intern Med. 1 April 1993;118(7):529-539.
42 - Phenylbutazone Carrier Formulation Showing Increased Bioactivity in Animals. United States Patient Application Publication, Gordon, January 27, 2001.
43 - Phenylbutazone Carrier Formulation. United States Patient, Green, April 22, 2003.
44 - Phenylbutazone Carrier Formulation. United States Patient, Gordon, February 8, 2000.
45 - Some Studies of the Formulation and Evaluation of Tablets with Special Reference to Direct Compression Sugars. Ondari CO. 1984 PhD Dissertation. University of Rhode Island.
46 - Phenylbutazone-sodium-monoglycerate in the treatment of inflammation. United States Patent, Urwyler, September 18, 1973.
Analgesic. antipyretic and anti-inflammatory agents. Insel PA. Goodman & Gilman's Pharmacological Basis of Therapeutics. AG Gilman, TRall,'A Nies & P Taylor; McMillan Publishers N.Y. Vlllth ed 1990: pp 638-681.
Deaths due to butazolidin. Br Med J. 1952;2:1427.
The Effects of Phenylbutazone on the Morphology and Prostaglandin Concentrations of the Pyloric Mucosa of the Equine Stomach. CL Meschester, M Gilbert, L Krook, G Maylan and R Corradino. Vet Pathol. 1990;27:244-253.
Fall/Winter Laminitis, www.equinemedsurg.com.
Medical treatment of osteoarthritis in the horse - a review. Goodrich LR and Nixon AJ. Vet J. 2006; 7:51-69.
NSAID Toxicosis in Horses. Merck Manual. www.merckmanuals.com
Phenylbutazone: Its Actions, Effects, and Role in Equine Medicine. Thomas Tobin. Modern Equine Medicine. January/February 1983. Page 25.
Phenylbutazone interferes with uptake of iodine by the thyroid gland. McEvoy GK. American Hospital Formulary Service - Drug Information 1999.
Thyroid glands in horses. Les Sellnow. thehorse.com. July 1, 1999.
Use and misuses of anti-inflammatory drugs in race horses. Hopes R. Equine Vet J. 1972; 7:66-70.