Comparing therapies for canine hyperadrenocorticism

Dr. Edward C. Feldman lectured at the 2007 American College of Veterinary Internal Medicine (ACVIM) Forum in Seattle on "Medical Management of Canine Hyperadrenocorticism: A Comparison of Trilostane to Mitotane." Here are some relevant points:

Polyuria is the most worrisome and life-threatening aspect of hyperadrenocorticism in the context of owners who will not or cannot tolerate a dog that is no longer housebroken due to large volumes of urine produced secondary to a condition like hyperadrenocorticism. Therefore, the concern that encourages most owners to consider treatment is their dog's polyuria.

No dog should be treated for hyperadrenocorticism — a clinical condition — unless there are obvious clinical signs consistent with the diagnosis and that are worrisome to the owner. But once a dog has clinical signs and the diagnosis is confirmed, the owner should consider treatment.

Medical therapy using o,p'-DDD

o,p'-DDD (Lysodren, Mitotane) is a cytotoxic agent related to the insecticide DDT. This drug has been used successfully by veterinarians for the treatment of canine PDH for well over 30 years. The drug has a reputation of being toxic, and that has has limited its use. However, that reputation for toxicity should merely increase respect for the drug. Used correctly, it is safe, cost effective and efficacious.

No dog with a poor appetite should ever be treated medically for PDH.

Induction protocol

Therapy with o,p'-DDD always should be initiated at home, with the owner administering 25 mg/kg, given BID. Glucocorticoids are neither routinely administered nor dispensed. Rather, the owner should receive thorough instructions on the actions of o,p'-DDD. Then, the owner is instructed to begin reducing the dog's food allotment by one-third beginning the day before o,p'-DDD is begun.

Because we always begin therapy on a Sunday, we have owners give their dog two-thirds of its normal food allotment, one-third each morning and again one-third each evening, beginning on the Saturday preceding the first day of therapy. This should make the typical polyphagic dog quite hungry.

Lysodren administration should be continued BID until any of the following are observed: 1) the polydipsic dog's daily water consumption approaches 60 ml/kg; 2) the dog simply takes longer to consume a meal and certainly if it develops partial or complete anorexia/inappetence; 3) vomiting; 4) diarrhea or 5) unusual listlessness. Any of these observations demands that an owner stop daily o,p'-DDD therapy and have the dog examined by the veterinarian.

The single most reliable and consistent indicator for having reached the endpoint of this induction phase of therapy is appetite reduction. Any reduction in appetite indicates that the induction phase has been completed. The water intake in polydipsic dogs may decrease in as few as two days or as many as 35 days (average is five to 14 days), but is less consistent in determining therapeutic endpoint. Using appetite to determine endpoint also decreases the risk of ever observing vomiting or diarrhea secondary to the use of o,p'-DDD.

Lysodren is quite successful in eliminating the clinical signs of hyperadrenocorticism by reducing serum cortisol concentrations. This therapeutic approach requires close communication between owner and veterinarian. Either a veterinarian or technician should call the owner each day beginning with the second day of therapy during the initial week, or induction phase, of o,p'-DDD administration. The owner, after being contacted several days in a row, typically becomes quite impressed by the veterinarian's concern.

They usually will begin to observe their dog closely. Once a dog demonstrates any reduction in appetite, it can be examined by the veterinarian. An ACTH-stimulation test can be done at that same visit. In addition to making daily calls, the veterinarian should see the dog no later than eight days after beginning therapy, if an owner has not seen appetite reduction. At this time, a thorough history, physical examination and an ACTH response test should be performed. Dogs responding clinically to the medication (or if the owner is not certain about response) should have further therapy withheld until results of the ACTH response test can be evaluated.

Therapy goals with o,p'-DDD are to achieve resolution of the clinical signs. This typically correlates with an ACTH response test that is suggestive of relative hypoadrenocorticism. Successful response to o,p'-DDD is indicated by pre- and post-ACTH serum cortisol concentrations >1.5 mcg/dl and <5 mcg/dl.

Maintenance therapy

The maintenance phase of therapy with o,p'-DDD should be initiated once a dog seems much improved or normal to an owner, or if a post-ACTH serum cortisol concentration is <5 mcg/dl. It is important to emphasize that each dog must be treated individually. Most dogs respond during the five- to nine-day induction period. It is unusual for a dog to require more than eight or nine consecutive days of o,p'-DDD, just as it is unusual for a dog to respond in less than four days.

About 20 percent of dogs with PDH are not polydipsic. They, too, should be treated by their owners at home.

Absence of polydipsia simply eliminates one of the factors that can be monitored during the initial phases of therapy.

Lysodren does not affect the pituitary gland or tumor. Therefore, the excessive ACTH secretion associated with pituitary-dependent hyperadrenocorticism continues or becomes exaggerated with therapy. Failure to continue o,p'-DDD therapy will result in regrowth of the adrenal cortices and return of clinical signs. This recurrence typically occurs within one to 12 months of stopping therapy.

Maintenance therapy involves choosing an o,p'-DDD protocol and altering that regimen as required clinically for each dog. Whenever possible, the weekly dose of medication should be divided into as many doses as possible. For example, if a 10-kg dog is to receive 50 mg/kg per week, rather than give that dog one 500-mg tablet once weekly, we give one-fourth tablet four times weekly.

In general, dogs that have post-ACTH serum cortisol concentrations <1mcg/dl have medication withheld for two weeks and then are placed on 25 mg/kg per week. Four weeks after therapy is started, an ACTH stimulation test should be rechecked. If the post-ACTH stimulation test result is 1.0-3.5 mcg/dl, 25 mg/kg per week should be initiated, with the recheck scheduled for four weeks later. If the post-ACTH stimulation test result is 3.5-7.5 mcg/dl, 50 mg/kg per week should be initiated, with a similar timing for the recheck. If the post-ACTH stimulation test result is greater than 7.5 mcg/dl, one should first be certain that the medication is being given. If being given, remind owners that the drug should be administered immediately after a meal since the medication is best and most consistently absorbed from a stomach that contains food.

If the owners are following these instructions, absorption can be enhanced by crushing the o,p'-DDD, and then suspending the powder in corn oil. That suspended medication should then be mixed into the food. Never raise the dose and use corn oil for the first time. Corn oil does enhance absorption of this drug.

The most important factor in dose determination is owner opinion, not some cortisol concentration after ACTH administration or some other laboratory result. With this in mind, the post-ACTH serum cortisol concentration should be used as a guide in determining whether a dose should be increased or decreased. If a dog is receiving one-fourth tablet of drug four times weekly, and it has a post-ACTH serum cortisol concentration of 1.3 mcg/dl, we would recommend lowering the dose to three times weekly and plan a re-check for three months later. If a similar dog is receiving one-fourth tablet four times weekly and has a post-ACTH serum cortisol concentration of 8.9 mcg/dl, we would recommend increasing the dose to five times weekly and schedule a recheck for three months later.

In this manner, the typical dog with pituitary-dependent hyperadrenocorticism is consistently being maintained without being overdosed or underdosed for any length of time.

Medical therapy using trilostane

Trilostane is an enzyme blocker that prevents the synthesis of cortisol. In contrast to o,p'-DDD, a cytotoxic drug, trilostane reportedly does not damage cells but is effective only until the drug is metabolized.

In the United Kingdom, trilostane is officially registered for use in dogs under the trade name Vetoryl. The product for use in humans is listed as Modrenal. The current recommended initial dose is 30 mg once daily for dogs that weigh 3 to 10 kg; 60 mg once daily for dogs weighing 10 to 19 kg; 120 mg for dogs that weigh 20 to 40 kg, and 120 to 240 mg for dogs weighing more than 40 kg.

Re-evaluations are suggested after one, three, six and 13 weeks, and then after six and 12 months. Each re-check should include a history, physical examination and an ACTH stimulation test. The ACTH stimulation test should be completed two to six hours after administration of the trilostane. The target range for serum or plasma cortisol concentration should be between 1 and 2 mcg/dl.

It is readily apparent that these dose recommendations result in tremendous dose disparity among dogs. A dog that weighs 3 kg, being given 30 mg once daily, receives 10 mg/kg, while a dog that weighs 20 kg receiving 120 mg would receive 6 mg/kg. A dog that weighs 40 kg could receive as little as 3 mg/kg. These dose disparities can result in severe negative side effects.

Experience at UC-Davis differs quite a bit from that in the literature and the United Kingdom. It is not clear why the results have not been similar. It seems that the most common reason for choosing this drug over o,p'-DDD is safety. In other words, trilostane has been viewed as much safer and, perhaps, more effective in controlling clinical signs of pituitary-dependent hyperadrenocorticism.

Some of the dogs we have treated have done remarkably well on a once-daily protocol. However, a significant percentage of dogs we have treated with trilostane have become ill (including deaths), either from glucocorticoid deficiency or from glucocorticoid and mineralocorticoid deficiency (hypoadrenocorticism). Some of the iatrogenic hypoadrenocortic dogs appear to have this condition permanently. In addition, treated dogs that fail to exhibit resolution of polyuria despite having ACTH stimulation test results within the recommended range do occur.

Therefore, trilostane is neither more effective nor safer than o,p'-DDD. Of greatest concern is that trilostane has been less predictable regarding underdose, overdose, resolution of signs or need for dosing more often than once daily.

The UC-Davis current recommendation is to initiate trilostane therapy at 1 mg/kg once daily. That dose is continued for about one week until a veterinary re-check can be completed.

Owners are instructed to collect a small urine sample from their dog before leaving home the morning of the scheduled re-check prior to trilostane administration. Trilostane should then be given and the dog should be seen by the veterinarian two to three hours later.

The goal of therapy is an owner who is completely pleased with the response. As aids in achieving this goal, both urine and blood tests are indicated. The urine should be checked, at a minimum, for specific gravity, glucose and urine cortisol-to-creatinine ratio (UCCR). An ACTH stimulation test should be started at the time the dog is seen, again about two to three hours after trilostane administration.

The UCCR result should be within the reference interval and the post-ACTH serum cortisol concentration should be between 1.5 and 5.5 mcg/dl.

If the serum-cortisol concentration is within that goal and the UCCR is abnormal, the medication should be given BID. If the serum-cortisol concentration is too high, the trilostane dose should be increased. But if the serum-cortisol concentration is too low, the dose should be decreased.

This approach should be used at each re-check until the dog is doing well.

Dr. Hoskins is owner of DocuTech Services. He is a diplomate of the American College of Veterinary Internal Medicine with specialities in small-animal pediatrics. He can be reached at (225) 955-3252, fax: (214) 242-2200 or e-mail: jdhoskins@mindspring.com