Canine hyperadrenocorticism: Which treatment should I turn to?

Psst, over here! We've got some guidance on how to treat hyperadrenocorticism. (Getty Images)So many bald, thirsty dogs ... So many drugs and doses to choose from ... Hyperadrenocorticism can be a confusing disease to treat in dogs, but it is possible to tailor treatment to the patient. The good news is that there are a lot of options for treatment. Here's some help clearing it up.

We can all agree that our goals for treating our patients with hyperadrenocorticism should be to:

• Address the primary cause of the disease if possible, a pituitary or adrenal tumor.

• Control those pesky clinical signs.

• Prevent treatment-related side effects.

• Keep treatment cost-effective for the owners.

Your treatment choices will depend on several the answers to several questions:

• How severely affected is the dog? (How bad are the clinical signs?)

• How quickly do you need to get control of the clinical signs?

• What other diseases does the dog have?

• What other medications is the dog taking?

Two more things to keep in mind when treating hyperadrenocorticism: First (and make sure that you relay this to your clients before beginning treatment or it could come back to bite you) not every dog will have resolution of every clinical sign. Second, there is no evidence that if a dog with hyperadrenocorticism that has no clinical signs is treated that it will live any longer than without treatment. So if you happen to diagnose hyperadrenocorticism incidentally and the dog is not exhibiting any clinical signs, the recommendation at this time is to not treat the dog for hyperadrenocorticism.

A quick Q&A

So mitotane or trilostane?

There is no evidence either way that mitotane or trilostane produces better a survival time than the other. In my analysis, the advantage of using trilostane rather than mitotane seems to be a lower incidence and milder forms of side effects of treatment.

If a dog needs a dose increase, do I raise the once-a-day dosage or switch from once to twice daily?

Here's what I do: If the clinical signs are not improved and the results of the serum cortisol concentration on the ACTH stimulation test are > 9 mcg/dl, I will raise the dosage by 25% to 40% and repeat the test in two weeks. I go to twice-daily dosing when clinical signs are not improving and the four-hour serum cortisol concentration is < 9 mcg/dl but the 24-hr serum cortisol concentration is above the normal range. In that case, I do not increase the total daily dosage; instead I take the once-daily dosage and divide that in half and give that twice daily to start.

Are these drugs given with or without food?

Remember that all three of these medications should be given with food because a meal increases their absorption. Also, most cortisol assays used these days are not affected by lipemia, so when performing an ACTH stimulation test, you need to make sure that the dog is fed as normal the morning of testing. This will prevent you from erroneously raising the drug dosage because of poor absorption that day.

So the dog has clinical signs, you have diagnosed hyperadrenocorticism (see my other article on diagnosis), and the owner has consented to treatment and monitoring if needed. What are your best and most common choices? Glad you asked!

Mitotane

Mitotane is also known as o,p'-DDD, and it certainly appears to me that the Food and Drug Administration (FDA) wants nothing to do with it. This is presumably because the Environmental Protection Agency (EPA) doesn't want anything to do with it. The FDA has classified mitotane as an orphan drug, meaning that they have mandated that the manufacturer has to keep making it until another pharmaceutical company produces a better drug able to be label-approved to treat your licensed indication--in this case for people, it is inoperable, functional or nonfunctional, adrenal cortical carcinoma.

So it will be available for a while, presumably. Great. But, bear with me a minute here, if you tell a client you are going to give their dog mitotane, good old Dr. Google will check in with that client and offer them the following information (as well as a free office call, no examination): Yes, mitotane is a derivative of the insecticide DDT. Yes, the EPA has classified it as a carcinogen. Yes, when it gets into the soil it stays for a very long time. Yes, it was originally developed as chemical warfare agent (but was unsuccessful in that endeavor because all it caused was adrenal necrosis). And, yes, I'm quite certain that your clients will tell you that it kills baby bald eagles. So now you have to tell the client, "Yes, that is all true, and I want to put your dog on this medication."

So why are you trying to kill their dog? Here's what you answer. Mitotane has been successfully used to treat hyperadrenocorticism in people and dogs since the 1960s. It is a chemotherapy drug, and killing certain cells is what it is supposed to do to try to fix your dog's problem.

Some studies have found a good to excellent response in 80% of patients with hyperadrenocorticism when treated with mitotane.1

However, one study found that that effectiveness decreased to 57% in controlling clinical signs when being used by general practitioners, rather than specialists.1 This decrease in effectiveness was found to be solely based on the dose administered. General practitioners tended to be dosing at much lower levels than the specialists. The reason given was that they were worried about creating undesirable side effects.

Regarding side effects, 20% to 45% of patients treated for hyperadrenocorticism with mitotane experience some side effects during induction or maintenance.1

Luckily, these are mostly minor gastrointestinal signs and easily managed by stopping the drug and starting again at a lower dose. When you do this, most dogs can eventually tolerate the treatment. However, 5% of dogs treated with mitotane for hyperadrenocorticism have been found to develop full-blown Addisons disease--not just glucocorticoid insufficiency, but mineralocorticoid deficiency as well which can be transient or permanent.1

If you've been using mitotane to treat your patients with hyperadrenocorticism long enough, you know that treatment eventually fails; their ACTH stimulation test results start to go back up. In fact, 58% of dogs receiving mitotane relapse on maintenance within the first year.1

This is because when you knock out most of the adrenal cortisol production, endogenous ACTH ramps up and causes any remaining adrenocortical cells to grow, so eventually adrenal hyperplasia returns. and then you have to go back through the induction phase of treatment again. What this should tell you is that it is super hard to completely kill the adrenal glands with mitotane.

Selegiline

Selegiline is a monoamine oxidase type B inhibitor (MAOBI). Monoamine oxidase is the enzyme in the brain that breaks down dopamine, so blocking it will raise the dopamine concentrations in the brain, which will suppress ACTH production. A big advantage to this form of treatment is that selegiline doesn't interfere with adrenal enzymes and is not adrenolytic, so monitoring is based solely on clinical signs; there is no hormonal monitoring recommended. That's right, you don't have to do ACTH stimulation testing and don't have to check electrolytes! This also leads to a significant benefit of a lower incidence of side effects than the other two common drugs used to treat hyperadrenocorticism.2

The recommended dose for starting selegiline treatment for hyperadrenocorticism is 1 mg/kg with food in the morning. If you don't see improvement in clinical signs in a month, raise the dose to 2 mg/kg/day. If you don't see improvement in another month, then discontinue this treatment because raising the dose isn't going to help this patient. It should also be noted that selegiline should not be prescribed in dogs receiving other MAOBIs, tricyclic antidepressants or selective serotonin reuptake inhibitors.

The efficacy of selegiline treatment in dogs with mild to moderate clinical signs of hyperadrenocorticism has been found to be 50% to 70%.2 In dogs with more severe clinical signs, it's only 20% to 30% because those dogs lost their remaining dopaminergic neurons.

Trilostane

Like ketoconazole and metyrapone, trilostane (Vetoryl--Dechra) is an adrenal enzyme blocker. But, unlike ketoconazole and metyrapone, trilostane is effective at blocking the adrenal steroid synthesis at the top of the cascade, so it blocks all three arms (glucocorticoids, mineralocorticoids, sex hormones). Thus, mineralocorticoid deficiency must be monitored for, as well. Monitor it the same way as treatment with mitotane, with ACTH stimulation tests and serum electrolyte concentrations, sodium and potassium concentrations in particular. After starting trilostane treatment, perform an ACTH stimulation test in 10 to 14 days, at one month, at three months and then every three to four months thereafter.

If you give a single does of trilostane to a normal dog, serum cortisol concentrations decrease rapidly and will stay down for about eight hours and then slowly creep back up. That is why it was standardized to do your monitoring ACTH stimulation tests four to six hours after trilostane administration. This window is the time of maximal adrenal suppression, and all of the material by which you base your judgment on trilostane dose adjustment are based on measurements taken during it. A note to consider when testing is that doesn't matter whether you draw your sample at four or six hours after trilostane administration, but it does matter that you do it at the same point in the window every time you test the dog.

If you have you trilostane compounded, it has been found that the concentration of the active ingredient in the formulations can vary widely. Also, it is my recommendation when using the manufactured product to ignore the dosages recommended on the label, as it is too high. In fact, the manufacturer is in the process of trying to get the label dosage revised. I recommend a starting dosage of 1 to 2 mg/kg once a day in the morning with food.

A side effect that can be seen in about one-tenth of one percent of dogs treated with trilostane, either acutely or later in treatment, is acute adrenal necrosis, causing Addison's disease. Experts think that rather than this being a direct toxic effect of the drug, trilostane causes the serum cortisol concentration to be so suppressed, the serum ACTH concentration becomes very elevated, causing the necrosis.3

References

1. Kintzer PP, Peterson ME. Mitotane (o,p'-DDD) treatment of 200 dogs with pituitary-dependent hyperadrenocorticism. J Vet Intern Med 1991;5(3):182-190.

2. Bruyette DS, Ruehl WW, Entriken T, et al. Management of canine pituitary-dependent hyperadrenocorticism with l-deprenyl (Anipryl). Vet Clin North Am Small Anim Pract 1997;27(2):273-286.

3. Reid LE, Behrend EN, Martin LG, et al. Effect of trilostane and mitotane on aldosterone secretory reserve in dogs with pituitary-dependent hyperadrenocorticism. J Vet Intern Med 2014;28(2):443-450.