Treating Cushings Disease with Mitotane ( Lysodren Rx)

Anipryl vs. Lysodren for Cushings treatment

Question: Dear Dr.Mike, Your Aug.'99 issue of VetInfo Digest stated that Anipryl, although expensive, was a possible tx choice for the pituitary- dependent form of Cushings Another website, around the same time, recommended it as the first choice to try. More recently, my friend's dog was diagnosed with Cushings, and she was told Anipril "didn't pan out" as a treatement for Cushings. What has been your experience, subsequent to your '99 article? Do you still think it is worth a try, if cost is not a major concern, before moving on to the more toxic chemotherapies such as Lysodren? Many thanks, Carolyn

Answer: Carolyn- At the present time the generally accepted opinion on selegiline (Anipryl Rx) is that it works very well in approximately 20% of dogs with hyperadrenocorticism, works acceptably well from the client's perspective in an additional 20% of dogs and doesn't work well for the remaining 60% of dogs. The information available on selegiline from textbooks has a pretty strong slant against the medication, possibly because two of the major textbooks have information from the same group of veterinarians who do not accept that the resolution of symptoms is an acceptable outcome if the lab values don't change ---- which is exactly what happens in most dogs with hyperadrenocorticism. This is enormously frustrating when trying to base treatment decisions on demonstratable evidence that the medication works. Veterinarians who do believe that selegiline works well enough to try look at the situation differently. Mitotane (Lysodren Rx) doesn't treat the underlying disease (except possibly when it is caused by adrenal tumors) any better than selegiline but it does change the lab values that are measured to determine if the disease is present. The question then becomes, which is more important, changing the lab values or making the patient comfortable? Looked at this way, it seems reasonable to try selegiline since it is easier to use and safer to use than mitotane. I think that there are a few things to think about when making this decision. First, it is pretty essential that the hyperadrenocorticism be pituitary in origin. Second, there shouldn't be life threatening problems associated with the Cushing's disease, like persistent urinary tract infections, persistent deep skin infections, secondary diabetes or any other serious complication. In these situations it is probably better to use mitotane because it works for about 90% of patients versus the smaller number that benefit from selegiline and it is possible to measure lab values to see if there is an effect, which is a lot more reassuring in these cases. I have clients who aren't going to try mitotane under any circumstance because they aren't going to bring their dog back to the clinic repeatedly for lab work and adjustments in therapy. Having selegiline at least offers these folks an option, which is the other reason that we will continue to use selegiline. Anecdotal evidence isn't always a good thing to relate, but my dog has Cushing's disease and she seems to be doing well with the use of selegiline over the last two years. Mike Richards, DVM 1/6/2004

Cushings in Chow - Bad Reaction to Lysodren

Question: Hello Doctor,

I am a suscriber and I come to you once again for some guidance. Macha, our 10 years old chow mixed has been diagnosed a few months ago with Cushing. We have followed our vet's suggestion of putting her on Lysodren. During the holidays, we have travelled to VA to visit family. There she stopped eating and started feeling weak. I have called the vet who told us to boost her with cotisone pills. We did that, unfortunately it turned for the worst as she began a severe episode of Addison. Knowing that something was very wrong with her, we cut short on our vacation and came back home. We dropped her off at the emergency where she was kept for three days. Talking to my vet today, i stated that I was really uncomfortable with lysodren now, to say the least, I fear it. It took us by suprised and we almost lost our dog. I now have to face the big choice of taking her of the drug and let nature follow its course or risking another episode such as the one we have known a few days ago. When cushing was diagnosed, i was told that it was a disease that can be easily controlled, nevertheless this episode has left us very bitter. I should say that she has never has, to my knowledge, any of the symptoms known to cushing. She was diagnosed before a minor surgery. I come to you today hoping you can give me a few words of advice on wether or not I should stop the lysodren treatment and what i should expect if she is not treated. Will she be more enclined to suffer from symptoms because she use to receive treatment? What is her life expectancy with treatment as opposed to not being treated?

Thank you for you reply, Louise

Answer: Louise-

I am reluctant to treat patients for Cushing's disease unless they have symptoms that are causing difficulties for them, such as increased drinking and urination, hair loss, muscular weakness, skin disorders and neurologic signs. My basic reasoning for this is that there isn't much evidence that treatment prolongs the life span of patients with Cushing's disease, if you don't count euthanasia due to problems like increased urination. So the major benefit of treatment is not prolonged life but comfort in the remaining life span. With this in mind, if there are no symptoms, there seems to be no strong reason to treat the disorder. On the other hand, there is good evidence that it makes patients with clinical signs feel better and some evidence that starting treatment early helps to control symptoms over the long run, so some vets feel differently than we do about when to treat.

There is an alternative approved treatment for Cushing's disease, which is the use of selegiline (Anipryl Rx), a medication that works well in about 40% of Cushing's disease cases and has less potential for harmful side effects and for causing hypoadrenocorticism (Addison's disease). It may be worth considering the use of this medication if there are future problems with clinical signs associated with Cushing's disease.

At the present time, most vets still favor the use of mitotane (Lysodren Rx) for the treatment of Cushing's disease, primarily because it is effective more often than selegiline but also because some veterinary endocrinologists question whether selegiline works at all, because it doesn't improve the results of standard tests used to assess the treatment of Cushing's disease even though it does appear to alleviate clinical signs in many patients. So your vet's choice of this medication is not really unusual. It is important to monitor for signs of hypoadrenocorticism and to know that it may occur when using Lysodren.

I have no problem with waiting until clinical signs appear before deciding to treat with Lysodren or Anipryl, since there isn't much evidence to indicate a longer life span when using these medications (there is a little evidence for this when using Anipryl, but only for one small subset of Cushing's disease patients). It would not bother me much if a client opted to discontinue treatment for this condition and see what happened, as long as they realized that we would have to repeat the initial stages of medicating, in which regular lab work (ACTH response tests) would have to be done to ensure that we have the correct dosages, when they decided to start the medication again due to the occurrence of clinical signs. I know of no evidence that suggests that stopping treatment and then restarting it is any more likely to cause problems or that there might be an increased chance that Lysodren would fail to work the second time around.

It would be best if you can schedule some time to discuss all this with your vet. The choice to use Lysodren was almost certainly made in good faith based on your vet's experiences with this disease and this medication. The outcome was scary for you and it was probably scary for your vet, too. I'm pretty sure your vet will remember this and inform future clients about the risk of Addison's disease when using Lysodren. I know that I have sometimes had to deal with a bad outcome prior to really understanding the risk of a treatment and properly conveying that to my clients.

Mike Richards, DVM 1/15/2001

Finding the Right Dosage of Lysodren for Husky

Question: Hi Dr Mike I just subscribed this week and have learned a lot about Cushings Disease. This is what my 13 yr old female Husky "Cody" has been diagnosed with this month. Three weeks ago she was put on Lysodren 2x/dy for a week . She did very well and seemed like her old self. Then on the 7th day she seemed to have a reaction or an overdose and we gave the prednisolone and no more Lysodren . He retested The test came back that she was just a little low. By then she was ok. My vet didn't want to start the 2x/week until 6dys after the the last pill . By the 5th day she was back drinking excessively and urinating constantly. On Monday she got one pill. But that night she was frantic for water and had to go out every hour all night. I gave her another pill Tuesday even tho she wasn't supposed to get another till Thursday. She was a little better. On Wednesday she was still drinking and peeing and by the evening she was completely frantic to get at water( which I removed for the night). Thursday morning she was laying in a pool of liquid. I gave her the pill she was supposed to get . That day she slept most of the day and was not drinking and peeing . I spoke to the vet about how up and down she has been on this dosage and that it has seemed to me that she hasn't been getting enough of the Lysodren in a week. He was reluctant to change it because of its toxicity and not wanting to overdose her. So we retested and it came back that she was a little low and not overdosed. He said to give her another pill that day ( Fri) So she had 4 pills that week and was still a little low.She does seem mentally foggy right after a pill and doesn't want to eat. After about 6 hours she usually comes around and wants a little food( but not dog food maybe some chicken or people food- She has never been that interested in food - She is about 48lb.) By Saturday night at 3AM she was frantic for water again, the worst I've ever seen her, trying to open toilets and jumping in the bathtub. I gave her another pill and within a half hour she had calmed down and stopped wanting to drink and went to sleep. Sunday she wasn't interested in food until the evening . Still urinating quite a lot over night and also in the morning I found a large pool of liquid with some food pieces in it- she must have vomited water. It was't bilious. This week the vet has suggested one and a half pills on Monday and again on Thursday. But I am having a difficult time sticking to the plan or understanding it since she gets better with more medication. I was wondering about a half pill per day. Wouldn't an even dosage be better than twice a week? She seems to be on such a roller coaster with the Lysodren. The other thing that I noticed is that these attacks for water and to have to go out to pee always happens after 10PM. My vet doesn't know any reason why this happens at night. What do you think about the dosage she's been getting and do you suggest anything different. I don't think she's been overdosed. We just don't seem to be getting the right amount of Lysodren to help her keep on an even keel. She's either frantic or sleeping . I'm anxious to hear what you think. "Cody's" mother, Carlye

Answer: Carlye- Mitotane (o-p,DDD, Lysodren Rx) selectively destroys two portions of the adrenal gland, the zona reticularis and the zona fasciculata. These areas of the adrenal gland produce cortisols which are elevated above normal levels in patients with hyperadrenocorticism (Cushing's disease, HAC)

In pituitary dependent HAC, the pituitary gland produces too much of the hormone that stimulates these areas of the adrenal gland, causing it to produce excessive cortisones. To stop this effect, mitotane is usually given in a dose that destroys enough of the adrenal gland to make it unable to produce too much cortisone but not so much that it can not produce any. Some dogs require a lot of mitotane (as much as 300mg/kg/week) and other dogs require much less, as little as 50 mg/kg/week. When the mitotane effect wears off, the adrenal gland hypertrophies and produces more cortisol again. This is the reason the medication is usually given on a twice per week basis, with a portion of the total dose given each time. There is no particular reason why the medication couldn't be dosed daily, except that you do not want to exceed the total weekly dosage necessary. Most veterinary clients just prefer to give the medication less frequently since that seems to work well for most pets.

The most important thing to remember is that you are trying to achieve a balance between the adrenal gland and the pituitary gland, in which the pituitary gland's excessive effect on the adrenal glands is balanced by you having killed enough of the adrenal gland that it simply can't respond to the pituitary gland and produce too much cortisol. If you overdose, you could kill off the entire adrenal gland, producing a state of hypoadrenocorticism (Addison's disease), which would also require life long therapy, but of a different nature. If this happens and is not noticed, it can result in the death of the patient, so there is reason to be cautious when using mitotane.

When mitotane doesn't seem to be working as well as expected, it is sometimes due to the presence of an undetected adrenal gland tumor, rather than pituitary dependent hyperadrenocorticism. Sometimes ultrasound exam or MRI examination can make it possible to diagnose an adrenal gland tumor that did not show up in the lab work usually used to differentiate between these conditions. If this odd response to mitotane continues you might want to check into this possibility.

An alternative approach to treatment of HAC is to give mitotane to the point that it kills the entire adrenal gland, on purpose. I have not tried this approach on purpose but did have one patient where this happened due to an error in communications with a client. The patient, a little poodle, did well except for the initial crisis in which it almost died, since neither the client nor I was consciously trying for this effect. We did have to treat this patient for life for the hypoadrenocorticism but she lived for several years and did well during that time. You should definitely not do this on your own. Your vet must be told that you have found it necessary to increase the dosage, since hypoadrenocorticism is life threatening.

It might also be a good idea to recheck for diabetes mellitus, since it sometimes occurs in patients with Cushing's disease and also to consider the possibility of another concurrent disease, such as kidney failure, liver failure or diabetes insipidus, which can cause excessive thirst, as well.

Cushing's disease is a very variable disease in its response to treatment and its effects on individual patients. It can be very hard to reach a stable point in which maintenance therapy has a steady dosage on a regular basis but it is almost always possible to get there, eventually.

Keep working with your vet and together you can figure out the best dosage and dosing interval for Cody.

Mike Richards, DVM 10/9/2000

Intolerance to Lysodren in dog with hyperadrenocorticism.

Q: Dear Dr. Mike, I am a Vetinfo Digest new subscriber. My dog Sable, age 13-1/2 is a chocolate lab who was diagnosed about three months ago with Cushings Disease, the pituitary variety. I believe she has been ill for over 6 months. She was started on Lysodren 500 mg bid and 20 mg prednisone by our regular vet and did this for 7 days. Then we went to see the "specialist" who changed the dose to 500 mg tid and no prednisone. She was to do this for 5 days. On Day 4 she began showing a lot of CNS troubles. It began with shakiness, progressed to stumbling and by the next day she was unable to stand. At this point I gave her 20 mg of prednisone and took her to emergency a few hours later. Her electrolytes were normal and they did the ACTH stim test. They sent us home with 10 mg of prednisone to be given once daily until we got the results. Four days later we heard that the ACTH test result was 3 and she should be taken off the Prednisone and should take Lysodren 750 mg 2 times a week. So the next day she got the 750 mg in the evening (Thursday). Friday night she slept thru the whole night, which she never does. And I woke her up on Saturday am at 5:00. She could barely hold up her head. She could not move. I finally got her to drink and eat something and gave her 10 mg Prednisone. A few hours later she could stand with help and could walk but was very ataxic. I did not take her in to the Dr. Instead I gave her 5 mg of pred at night and did the same on Sunday-10 mg in thea.m. and 5 mg. at night. ON Monday I spoke with the DR. HE said, to stop the pred and just go to 500 mg of Lysodren in divided doses two times a week.after letting her rest the whole week. So on the next Monday (8-2) I gave her 250 mg Lysodren in the a.m. By afternoon she seemed a little wobbley so I only gave her 1/4 of the pill. Tuesday 2:30 a.m. she is stumbling around again so I give her 10 mg of pred and by 5:30 a.m. she is better. I talk to the Vet. He now says that she cannot tolerate the Lysodren at all and he sees this as a reaction to the medication . He recommends that she not take it at all. He is not a promotor of Ketoconazole or Anapryl. So he says we have no hope. Are CNS side effects common with Lysodren and is giving Prednisone good to help combat this during the period when the dog is taking the LYsodren..Is this safe to do? She seems to be better when she takes the Pred after the LYsodren.. IS there any danger in continuing to do the Lysodren, maybe at an even lower dose? I would be willing to put up with a day of Sable stumbling around if this was going to help her problem. Incidentely, she is an otherwise healthy dog--no heart or kidney problems. She does have bad knees from arthritis and two blown cruciates and laryngeal paralysis. I know she is old but I just can't give up so quickly. Thankyou for your time Jennifer

A: Jennifer-

Sable may be having one of several problems.

A small group of dogs who are put on Lysodren for pituitary dependent hyperadrenocorticism appear to have a rapid growth of the pituitary tumors. The theory for this occurrence is that the sudden suppression of adrenal hormone leads to a rise in ACTH levels, which over-stimulates the pituitary gland and leads to a rapid growth in tumor size. I do not know why some dogs react in this manner and others do not. It is possible that it is just coincidence that mitotane treatment is started at about the time the tumor starts to grow rapidly. The growth of the tumor leads to neurologic signs.

In other dogs, mitotane directly causes neurologic signs as a form of drug reaction. In these dogs, clinical signs of neurologic disease should disappear within a day or so after the administration of the mitotane. Usually these signs develop during the maintenance period of the medication and splitting the dose up helps. This is what the specialist recommended based on your note, but it didn't work. It is possible to split the dose up even more and give it three times a week and in some dogs, a lower dose will still provide reasonable control of the hyperadrenocorticism.

I don't understand the reluctance to try selegiline (Anipryl Rx), ketaconazole (Nizoral Rx) or even radiation treatment or surgery. In my opinion, the choice of whether or not to pursue these options is yours, not the vet's. If he is unwilling to pursue them he should be willing to refer you to someone who will. It is true that the success rate for these four options is probably less than that of mitotane. But each of these treatments has clinical studies that support their effectiveness in some patients. Since mitotane appears to be difficult for Sable to take, what harm is there in checking out the other options? I think this is particularly true for selegiline, since it is unlikely to be harmful, even if it isn't successful. Its cost can be difficult for some owners to handle but that is again your decision, not your vets.

I am a little confused by the report on the ACTH stimulation test. As I understand this test, the goal of treatment with mitotane is to produce a resting cortisol level of less than 4 ug/dl and a stimulated level that doesn't rise much from this level. So a preACTH level of 3 ug/dl and a post ACTH level of 4 ug/dl would be pretty good. Or a preACTH level of 3 ug/dl with a post ACTH level of 3 ug/dl would also be good. If this is the case, then it seems to me that there is a small chance that the signs you have seen are the result of the suppression by mitotane leading to signs of hypoadrenocorticism (Addison's disease), which can include wobbliness and incoordination in some dogs. If this is the case, then prednisone would be helpful and might have to be maintained for a few days until the adrenal glands recovered sufficiently to produce normal cortisol levels again.

At this point, I really think I'd consider changing specialists, unless you are unwilling to pursue other treatment options, too. The best option might be to ask for referral to the veterinary school in Michigan. I just can't understand the reluctance to try other available options for a pet whose owner wishes to pursue them and has taken the time to understand the odds.

Mike Richards, DVM 8/4/99

Anipryl vs. Lysodren

Q: : MY 12 YEAR OLD ENGLISH SETTER, EDGAR, HAS BEEN ON LYSODREN THERAPY FOR ABOUT 2 YEARS. OF LATE, A TWICE-WEEKLY DOSE OF LYSODREN SEEMS NOT QUITE ENOUGH, THRICE-WEEKLY SEEMS TOO HARSH. I AM EXCITED ABOUT WHAT I'VE READ ABOUT ANIPRYL. EDGAR SEEMS OK MUCH OF THE TIME. HE DOES GET BLADDER/URINARY TRACT INFECTIONS FREQUENTLY; IS THIS BECAUSE OF LYSODREN? HE TAKES OMEGA 3 FATTY ACIDS, VITAMIN C, AND BIOTIN ON A REGULAR BASIS; HIS COAT AT THIS TIME IS VERY HEALTHY AND SOFT. SKIN-WISE HE HAS SEVERAL LIPOMAS-- THUS FAR HARMLESS? HE DOES SEEM TO BE GETTING MORE SMALL BUMPS OR LUMPS LATELY. HE DRINKS MORE WATER AND PANTS MORE THAN I THINK HE SHOULD, BUT I'M NOT SURE IF I'M HYPER-SENSITIVE OR NOT.

AT WHAT POINT DOES ONE SETTLE FOR A LYSODREN DOSAGE AND STAY WITH IT? HOW FREQUENTLY SHOULD I DO THE ACTH TEST, ETC? SHOULD I BE RELATIVELY CONTENT CONSIDERING HE IS 12 YEARS OLD AND HAS BEEN ON LYSODREN 2 YEARS? IS ANIPRYL ME JUST HOPING FOR A CURE/MIRACLE THAT MAY BE A PIPE DREAM? I FEED SENIOR SCIENCE DIET/CYCLE SENIOR CANNED FOOD; I MUST CONFESS TO TABLE SCRAPS MORE THAN RARELY! F YOU THINK A DIET CHANGE MAY HELP, LET ME KNOW. CAN I CONTACT DR. DAVID BRUYETTE DIRECTLY? ANY SUGGESTIONS ON HOW I CAN ASSIST MY VET BETTER? NY SUGGESTIONS ON HOW TO FIND OUT ABOUT ANIPRYL FROM A DOG/OWNER POINT-OF- VIEW VS. DRAXIS HEALTH? THANKS AND SORRY FOR THE INCOHERENCE! D.

A: It does sound like you a doing pretty well with the Lysodren treatment I am not aware of cystitis or bladder problems associated with the use of mitotane (Lysodren Rx). I do not know of specific dietary recommendations for dogs with this disease except a general recommendation to limit dietary fat, but there may be some. I do not think it is a major problem to give table scraps -- just avoid giving high fat ones.

I would be unhappy if thrice weekly administration of mitotane was necessary and would want to explore other options.

Dr. Bruyette can probably be reached at his practice, Veterinary Internal Medicine Specialists, in Kansas City, KS or through Deprenyl Animal Health, Inc. of Overland Park, KS. In the past he has always been willing to talk to people with an interest in l-deprenyl, or their vets. If you can't get the phone numbers from information operators, l et me know and I'll try to find them. That could take a while, though :)

l-deprenyl is available now in the U.S., under the brand name Eldepryl. It only works in pituitary dependent Cushings disease.

Hope this helps.

Mike Richards, DVM

Lysodren for Cushings

Q: My 12 year old Maltese was diagnosed with Cushings the first of April. He has been taking Lysodren (daily 10 days, 2x wkly since). His alkaline phosphatase is now 1500, up from 1108 on Apr 1. the Vet did not retest until June 13. I now realize (from the various Web articles I've read) that retesting should have been done sooner. Have you had experiences with a similar situation? Any opinions? I live in Dallas, TX. Any opinions on speciality vets here who deal with Cushings?

A: Teresa- It is not unusual for dogs with Cushings disease to have high alkaline phosphatase levels --- often in the range of your Maltese. This doesn't always resolve with therapy but our experience has been that it rarely indicates a clinically serious problem. I know that there are good veterinarians on the staff at Texas A&M, if your vet does not know of a specialist closer.

Mike Richards, DVM

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