Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Some things are best described by stating what they aren't. In the case of non-steroidal anti-inflammatory drugs, the non-steroidal cognomen refers to the fact that the agents in question are not steroids. The distinction is an important one, because steroids are associated with certain qualities and adverse effects, and classifying a drug as non-steroidal relays the immediate understanding that its actions and side effects are distinguishable from those of steroids.
Anabolic steroids have reached public awareness because of their abuse by athletes. However, the other and larger class of steroids is corticosteroids. These drugs have potent anti-inflammatory effects and a broad range of application in equine medicine. They are related to cortisone (a corticosteroid hormone and a precursor to cortisol found in small quantities in the adrenal cortex), and they have in their names the same ending (-sone or -one). Dexamethasone and prednisone are two common anti-inflammatory steroids that are effective in horses for reducing muscle soreness and controlling certain autoimmune conditions, insect hypersensitivities, and other problems.
Some steroids, like triamcinolone, are administered directly into the joints of horses with pain from osteoarthritis. The drugs reduce pain and swelling and decrease the activity of certain aspects of the immune system. However, administration of corticosteroids has been associated with development of laminitis, a complication that is not common, but that can have serious sequelae.
Non-steroidal drugs also effectively decrease inflammatory processes, but they act via different pathways and are associated with different drawbacks. They give relief to untold numbers of horses in many circumstances. But NSAIDs, like anti-inflammatory corticosteroids or any other drug, can wear white hats or dark hats. How well the person administering the drug knows the therapeutic applications and the potential adverse effects determines the difference.
How NSAIDs Work
Non-steroidal anti-inflammatory drugs impair the inflammatory process by inhibiting the enzyme cyclooxygenase (pronounced cyclo-oxygenase). Cyclooxygenase converts arachidonic acid, derived from the membranes that surround cells, into molecules called prostaglandins. Prostaglandins participate in generation of inflammation and fever. They are involved with the muscle soreness and stiffness that develop after an overstrenuous workout, the swelling and tissue deformation associated with injuries like bowed tendons, and fever in a horse with influenza. In horses with degenerative joint disease, prostaglandins contribute to the chronic inflammatory responses of joint effusion (fluid escape) and pain that result in a shortened stride or limp.
The prototype NSAID is aspirin. Aspirin is not useful as a fever- or pain-reducer in horses like it is in humans, but veterinarians might prescribe it in conditions when they want to block platelet activity. The two drugs in the NSAID class most familiar to horsemen are phenylbutazone and flunixin meglumine (the first commercially available brand of the latter was Banamine). These drugs rightfully enjoy a top-shelf place in the tack boxes or medicine kits of many horse owners.
The NSAIDs in your own medicine cabinet might be aspirin, acetaminophen (Tylenol), ibuprofen (Advil and others), ketoprofen (Orudis), or naproxen (Aleve). Drug manufacturers can alter the basic drug molecules in a given class of compounds by changing molecular structure in a minor way, and the new creations are given proprietary names, but the action common to all drugs in this pharmacologic group is cyclooxygenase inhibition.
Completely shutting down inflammation is not always the goal, however. It must be remembered that inflammation is the process by which the body heals a breach in its structure or contains infection and destroys the disease-inducing microbes. The pain that accompanies a tendon injury forces the horse to unload the affected limb and rest the structure while the cellular repair mechanisms go to work. In the case of fever, inflammation makes invading viruses or bacteria uncomfortable, too. The idea is the host organism rests and rides out the feelings of malaise, while the unbelievably complex and elegant components of the immune system do their jobs. Fever helps the body trap the invading microbes.
Not only is the inflammatory response itself designed with the host's eventual well-being in mind, certain products of cyclooxgenase are actually necessary parts of the body's so-called housekeeping activities--all the necessary reactions and cellular functions that are operant without our knowledge or conscious control. It's when we impair the synthesis of those compounds along with the inflammatory mediators that we start seeing signs of toxicosis from NSAIDs.
It is 7:30 a.m., and I am on my way out the door to the first scheduled stop of the day when the phone rings and the receptionist gestures for me to not leave while she writes on a notepad. She hangs up and tells me that I'll have to re-route the schedule to accommodate the upset owner who just called. Her new filly, which arrived on a van from two states away last week and is residing in a quarantine barn, didn't eat her feed this morning. The filly's rectal temperature is 106.4¢ª F, higher than any reading the owner had seen before. Now the filly looks stiff, is coughing, and is growing increasingly depressed.
My physical examination of the filly confirms the high fever. The history of a recent transport episode and the filly's young age makes thoracic disease the most likely, and the two most likely candidates are influenza virus infection and pleuropneumonia (sometimes called shipping fever).
Evaluation of the filly's lung sounds with a stethoscope didn't reveal any abnormal sounds that suggested the thorax contained fluid or that the lung surface was inflamed (in this condition, called pleuritis, the lungs make a distinct low-pitched rubbing sound against the inner surface of the chest wall as they expand and contract during breathing). I collect some blood to analyze back at the lab, and I evaluate the filly's chest with ultrasound. There is no fluid in the thorax, and the lung fields appear normal, suggesting the filly isn't battling pleuropneumonia.
Before leaving to return to the lab and analyze the blood, I give the filly an intravenous (IV) injection of flunixin meglumine, advise the owner to leave her in the isolation stall, and to avoid contact with any other horses after handling the filly. Fifteen minutes after my departure, the NSAID is doing its work: the filly brightens somewhat and begins to nibble at the hay in her feed rack.
The complete blood count (CBC) indicates some of the classic features of viral infection, and I call the owner and let her know that the infection is most likely influenza or another respiratory tract virus (isolation of the virus from nasal or pharyngeal swabs is needed before making a certain diagnosis). I instruct her to give the filly 1 gram of phenylbutazone orally every 12 hours and record the rectal temperature for the next 48 hours, after which I'll call back and re-examine her.
Administering a corticosteroid might also have been effective at breaking a fever and making the filly feel better, but it would have been inappropriate to use a steroid in a horse battling a viral or bacterial infection because of the immune-suppressing effects of corticosteroids. Non-steroidal anti-inflammatories are typically effective and safe to give horses with fever, as long as they have been eating and drinking and have no clinical signs of dehydration. Two days later, the filly's temperature had returned to normal range and a repeat CBC confirmed the white blood cell distribution was also returning to normal.
Non-steroidal anti-inflammatory drugs were helpful in one other patient I saw that day. I examined a mature Quarter Horse gelding with osteoarthritis in the knees, the result of a long athletic career. That horse's owner gives a 2-gram dose of phenylbutazone once daily for three to four days, when the horse seems particularly stiff. The anti-inflammatory drug augments the effects of the oral glucosaminoglycan supplement and physical therapy that the owner provides. After a lameness examination and collecting some blood to ensure that his kidneys were healthy, I dispensed another supply of tablets.
These two horses were good examples of the kinds of situations in which NSAIDs confer beneficial effects. A veterinarian can leave the premises in these situations knowing she has made a horse feel and perform better.
To understand the scenarios in which these drugs cross the line from helping horses to harming them, we revisit the concept that all components of an inflammatory response are not necessarily deleterious. Cyclooxygenase also generates prostaglandins that protect important mechanisms of normal physiology, the most important of which are maintaining blood flow to the cells that form the inner lining of the stomach, and sustaining blood flow to the kidneys. At no time are those protective functions more important than when a horse is dehydrated, in shock, or in other circumstances in which the blood volume coursing through certain capillary beds is decreased. The protective functions are the body's backup plan for when such episodes arise.
However, when a well-meaning human comes along and sees a horse that looks like it could use some pain relief, but doesn't recognize that the horse's circulation is compromised, administration of NSAIDs can harm more than help. The action of the NSAID turns off production of the prostaglandins that are helping ensure that the stomach lining and kidneys get their fair share of the cardiac output in these adverse circumstances.
Most people know taking NSAIDs can result in gastric ulcers. The highly acidic environment in the gastric interior is necessary to begin the process of digestion, but how do the cells themselves survive in an environment so acidic that it would corrode pipes? Those cells' survival depends on a layer of bicarbonate-rich mucus that coats and buffers them from the acid. Generation of the protective bicarbonate and mucous layer is directly and sensitively affected by blood supply, which, in turn, is sensitively controlled by vasodilatory prostaglandins.
When we give a dehydrated horse (or a normally hydrated horse) a twice-daily course of phenylbutazone or flunixin over a long period of days with the intention of controlling inflammation or pain, we are also undermining the physiologic mechanisms that protect the stomach and kidneys. This is true whether the drug is given orally or intravenously.
In the kidneys, the toxic effects of NSAIDs can manifest as renal papillary necrosis, which means that cells in certain parts of the kidney cease functioning and die. Externally, this might be recognizable as the horse urinating more frequently than normal or becoming unable to concentrate urine. Blood tests and urinalysis can indicate whether kidney function has been impaired.
Colonic inflammation is the third well-known manifestation of toxicosis seen in some horses that are treated with NSAIDs. The segment of large colon called the right dorsal colon is affected in this disorder, and the disease is a long-term and serious threat to well-being or even survival. Damage to this portion of bowel can lead to chronic protein loss and inflammation; the condition can be difficult to diagnose with certainty, and medical management is costly and prolonged. In some horses, surgical removal of the affected colon is necessary for survival.
Some horses not treated with NSAIDs also develop right dorsal colitis.
Over and above the innate toxic effects of these drugs, the other source of potential harm from NSAIDs is misuse by humans. It is useful at times to combine NSAIDs or to increase the dose, but careless or routine increasing of therapeutic doses can take a substantial toll on the horse's health. At no time is this more true than in a horse that has become dehydrated through various circumstances--a horse on an endurance ride, a colicky horse that hasn't eaten or drunk water for hours, a horse on a long trailer ride--and receives one or more doses of NSAIDs. It is important to avoid dosing these drugs inappropriately in such situations because the likelihood of causing problems is much more relevant.
The Multimodal Approach to Pain Management
Veterinarians are using multimodal pain control with increasing frequency in caring for horses with pain. Multimodal treatment refers to administering multiple classes of pain-controlling drugs instead of administering a single drug to horses.
With multimodal therapy, several different classes of pain-controlling drugs are administered. Administering multiple medications might seem off-putting, but the premise of multimodal therapy is increased effectiveness with a concurrent increase in safety.
Giving drugs, including NSAIDs, that work via different pathways enables lower doses of each to be given; the toxic effects of any given drug can, therefore, be avoided as the horse enjoys greater relief from pain. Non-steroidal anti-inflammatory drugs play an important role in such protocols, including formulations designed to be applied topically. Topical preparations permit the horse to receive high local concentrations of drug while avoiding the harmful systemic effects.
The guide to rational use of NSAIDs--or any other medications--is to remember that whatever process we are seeking to disrupt is likely to have other functions that are helpful, a maxim that holds true for inflammatory conditions. However, chronic or severe pain can be self-perpetuating and damaging, and NSAIDs can be very instrumental in improving the utility and quality of life for affected horses. Just remember to give the lowest dose possible for the shortest period of time in order to reduce side effects of NSAIDs.
About the Author
Dr. Kim A. Sprayberry, DVM, Dipl. ACVIM, is an internal medicine specialist at Hagyard Equine Medical Institute in Lexington, Ky. When not working with horses, she enjoys pursuits in medical journalism and editing as well as kayaking and American southwest archaeology.