Phenylbutazone(PMZ) - My Investigation and Questions concerning its use with certain Laminitic and Metabolic Horses.

Link to Article on Research Gate.

Link to Article at American Farriers Journal.



Phenylbutazone(PMZ) - My Investigation and Questions concerning its use with certain Laminitic and Metabolic Horses.

by Esco Buff, PhD, APF-I, CF

Currently, many of the laminitic horse's 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 owner's judiciously giving bute on their own in order to help with pain relief for their horse. It is not uncommon to hear that many of these horse's are on 4 to 8 grams of veterinarian prescribed or owner given bute a/day for weeks on end.

Over the last few years, I have experienced several horse's on high doses of bute, die from renal (kidney) failure. One of my mentors, George Platt, DVM, used to talk repeatedly about getting horse's off bute as it masks pain and because he found that horses recovered quicker when not on bute.1,2,3,4,5 I would have to say that my own personal experiences seemed to validate his comments in general although I have seen horse's on low dosages of bute recover without any issues.

Therefore, I took to the telephone, library and internet to do a little more investigative research on bute and it's use. 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 toxicity issues that bute may have. I found that overdose with bute can occur relatively easily if recommended medical doses are exceeded.6,7,8,9,10 One of the most common issue that many people are aware of, is the gastrointestinal issues from long term or higher doses of bute have on horse's.6,8,11,12 Bute is also the most toxic of the NSAID's (NonSteroidal Anti-Inflammatory Drugs).9 Looking into the bute toxicity relevant to the laminitic horse's work on, I found that the toxic effects of bute are related to the dose given and horse's that receive more than 0.4g/100 lbs of body weight per day for 4 days (4 grams to a 1000 lb horse) develop toxicity.13,15 Research results also suggests that that higher doses of bute is not associated with greater analgesic effects.14

One article noted that one US study found that horses on the maximum 4 grams/day oral regime for only four 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 toxicity is clear, the research validates that no horse should exceed the 0.4g/100 lbs of body weight per day for four days or more or risk possible toxicity issues. As a farrier then, what should I do when I walk into these situations when horses are being given 4-8 grams/day of bute? If the horse owner is administrating the bute, then I would think it would be most advisable to inform the horse owner that they shouldn't be administrating the bute without veterinarian approval and dosage recommendations. What if the veterinarian is the one prescribing toxic levels of bute? I can tell you from personal experience that private conversations expressing my concern for the high level of bute does not go over well.

The question becomes, why are the majority of laminitic horse's I'm called in to provide farrier treatment for are 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 horse's.

There is some humane justification for pain reliever's judicious use, 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, will ameliorate foot pain and create a more comfortable looking horse, but again the disease is not unabated.17 This creates an ethical dilemma, balancing the need to alleviate pain and suffering against the realization that most of what is administered is only palliative.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 horse’s current condition, provide an accurate mechanical treatment evaluation, and sometimes interferes with the monitoring of the horse’s progress. I have also witnessed horse's whose pain have been so masked that they continued to further damage their feet by stall walking more, decreasing foot pumping and weight shifting or kept them on their feet instead of possibly laying down to rest at times.

As a farrier dealing with many laminitic/foundered horse's, I personally look forward to the results of the clinical trails being done by University of California - Davis on the EH inhibitors.19 This could very well 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 the use of any pain masking drugs should be used carefully and judicially. 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 by veterinarian's.

The next issue I found in the research has to do with butes effect at lowering thyroid blood levels causing false low results by significantly decreasing T4 (thyroxine) and fT4 (free thyroxine) concentrations.20 Phenylbutazone has also 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 even aware that bute might be lowering their horses’ thyroid levels.23 In a 2006 proceedings paper for the AAEP, Nicholas Frank, DVM, admitted 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 use of Phenylbutazone.23,24

Therefore, to deal with this issue, thyroid hormone supplementations such as levothyroxine is used. Nicholas Frank, DVM does feel that thyroid supplementation does have some pharmacologic effect on horses, and his research shows that 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 of benefit. Unfortunately, this is not the case in may laminitic horse's I provide farrier treatment for.

The conclusion on thyroid level reduction show that bute clearly effects thyroid levels in horse's. This would especially be of concern with laminitic IR, EMS and PPID horse's. Thyroid supplementations has 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 horse's with bone degeneration can be a frustrating part of veterinarian and farrier treatment due to the constant pain many of these horse's are experiencing. There are several medical and mechanical treatment options that can be provided. During my investigative research, I found an issue with bute being utilized in these types of cases.
Drugs that help control pain, NSAID's (non-steroidal anti-inflammatory drugs) like bute, inhibit bone healing.26 Data on bone healing and NSAID administration has primarily been generated from rodents and rats.26 Nonetheless, this point seems clear: NSAID, when given at high doses and for long durations, negatively impact bone healing.26,27 Bone healing rate in horses is decreased with the use of bute.28 Whether the effect of NSAID's on bone healing is clinically important or not remains controversal.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. Another reason why EH inhibitors may be desired.
Further investigations revealed that due to phenylbutazone's serious adverse effects, it culminated in its unavailability for any human use in the United States. Phenylbutazone became available for use in humans for the treatment of gout and rheumatoid arthritis in 1949. Currently, it is not approved or marketed for any human use in the US.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 sicknesses.29,34,36

Phenylbutazone is a widely used pharmaceutical in the equine industry due to its availability and relatively inexpensive cost. For animals, bute is currently approved for oral and injectable use in dogs and horses. It is not approved for any food producing animal and its labeled use in horses is limited to horses not intended for food.31,37,38
In humans, Bute causes decreases in blood glucose levels and fasting hypoglycemia.29,34,39,36,40.41

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 because unlike natural sugars, they do not promote significant tooth decay (shown in humans).45 Examples of natural sweeteners include but are not limited to, sucrose, glucose, fructose, lactose, acesulfame-K, dextrose, and sucralose. Xylitol, a natural sugar alcohol sweetener, lowers blood sugar (hypoglycemia) dangerously in dogs and sometimes humans.46

The conclusion 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), then this could be problematic for the IR and EMS horse. Research has shown that sugar ingestion in horse's causes increases in insulin levels. Looking into bute's high potency sweeteners and binders, I'm not aware or could not find any research on their effect with horse's. 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 was found, then the bute should be eliminated.

In conclusion, I think there are several considerations of bute use in IR, EMS and PPID laminitic horse's. 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 judicially and limit the indiscriminate use of bute for pain masking. The fourth is since bute clearly lowers thyroid levels, the horse should be on thyroid hormone supplementation. The fifth is that another pain relieving drug may be warranted in chronic laminitic horses due to the use of bute inhibits bone healing. The sixth is that blood glucose levels should be tested in IR, EMS and PPID horse's and bute discontinued if it causes hypoglycemicia.


References:

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, p22.
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 Oct42 (10):1754-9.
12 - Effects of toxic doses of phenylbutazone in ponies. MacAllister CG. Am J Vet Res. 1983 Dec44(12):2277-9.
13 - Phenylbutazone toxicosis in the horse: a clinical study. LG Colins and DE Tyler. J Am Vet Med Assoc. 1984 March 15184(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 Jan54(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-Dec11(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 200620:371-376.
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 201024:467-475.
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. 201023(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 May61(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. 201048:1270-1274.
32 - Aplastic anemia from veterinary phenybutazone. Ramsey R and Golde DW. JAMA. 1976236:1049.
33 - Misuse of veterinary phenylbutazone. Carpenter SL and McDonnell WM. Arch Intern Med. 1995 June 12155(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/BloodSugarControlRelatedDiseasesDeficiencies.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 1993118(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.


Other Resources

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. 19522:1427.

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. 199027:244-253.

Fall/Winter Laminitis, www.equinemedsurg.com.

Insulin, http://medical-dictionary.thefreedictionary.com/insulin.

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.