Diane Newman: Welcome. I'm Diane Newman. I'm an editor on UroToday.com. And on my bladder health center, we're pleased to welcome Dr. Jeannette Potts, who's a physician at Vista Urology in San Jose, California. She's also an expert in lower urinary tract symptoms. And today she's going to talk about nocturia opportunity here for treatment. And this is the third part of a three-part series. Welcome, Dr. Potts.

Jeannette Potts: Thank you, Diane. So in the opportunity, we can make a diagnosis, because again, nocturia is not a diagnosis. So this is a wonderful reinforcement of why we all went into medicine. So we can actually make a diagnosis and then we can find a cure. And ultimately, this condition helps us to become better medical practitioners. So in order to make the diagnosis, we need to emphasize to the patient how important sleep is, because sometimes our patients may not complain of nocturia either, just thinking it's part of being old. So we do want to always ask about sleep. And then we want to understand, as I alluded to in earlier talks, what do we mean by nocturia? Is the person actually getting up first and then deciding, "Oh, I might pee"? Or are they really being awakened from sleep, because their bladder is full or gives them a sensation of urgency.

Are we getting voiding diaries? What does the voiding diary show? And most importantly, what is the underlying cause? If we do find that there is nocturnal polyuria, what is actually causing this? In the meantime, while the evaluations are taking place, we can ask our patients to try conservative or behavioral interventions. They're all going to be helpful and they're not going to hurt anything. So exercising has been shown to help with sleep, especially consistent exercise that's done in early or midday, not before bedtime. Weight loss may decrease the risk of diabetes and decrease the risk of sleep apnea. Actually, it's a good treatment for sleep apnea as well. Sleep hygiene, sleep hygiene refers to the behaviors and rituals that we have before we go to bed. There are so many things that are kind of common sense and a lot of us still don't even follow them.

I mean, checking your emails before bed, probably not a good idea. Watching the 11 o'clock news, not a good idea. So these sorts of things need to be reinforced. Salt restriction, fluid restriction, especially in the evening hours. Leg elevation helps some people. If the legs are elevated above the level of the heart, maybe for an hour or two before going to bed, if someone is reading or watching a television show, that might help mobilize some of the fluid before going to bed. And bladder retraining if someone does have a lower capacity. Maybe if they're practicing during the day to have a little increase to their bladder capacity, that may translate into fewer episodes of nocturia. And now, we'll just go over pharmacological interventions, some of which I kind of disagree with, because I'm not sure what the indications are.

First of all, 5-alpha reductase inhibitors, we know that they're used to shrink the prostate volume. And remember, a 20% decrease in volume overall, which is the best that can be expected, doesn't necessarily translate to a 20% reduction in outlet resistance. There is no meaningful difference in nocturia when this medication is used. And it's an adjunct typically for the alpha-blocker to relieve some of the bladder outlet obstruction. Alpha-blockers, again, they're to target the bladder outlet resistance, decrease that tone of the prostate smooth muscle. Improvements for nocturia range from 0.3 to 1.1 episodes per night, more accurately, a decrease in voiding episodes by that fraction or by that number. Is that meaningful? It could be and maybe in the right patients, because again, that's the averages. I do caution all of us to be aware of the patient who self-reports that he is improving with or without therapy.

In those cases, sometimes the patient has bladder decompensation and is simply accommodating a larger post void residual. So for long-term management of patients, I always recommend a repeat Doppler or ultrasound in the office just to ensure that this is not occurring. It's really tempting not to do that when patients say, "Oh, by the way, I'm getting up much less these days." It could be just because their bladder capacity is accommodating. And not in a good way. Then there's the issue of combining alpha-blocker with anti-muscarinic. I admit when this first became an option, about 20 years ago, I was a little bit hesitant. But with caution, I became very comfortable using this in select patients. Nevertheless, here's this study with 879 men randomized. And the improvement with this combination therapy was deemed significant. But look at what significant meant. Decrease the voiding episodes by 0.59 versus placebo 0.39.

And so again, here's the caution, understand when statistical significance really has no clinical significance. And this is also the sad thing about so many studies, is that what did the voiding diary show with these men? Because again, I think we all know in our own practices, there are select patients in whom we realize they've got these two things going on. You can tell through the bladder diary. And then you're going to monitor them the first two to four weeks that you start them with the anti-muscarinic in combination with the alpha-blocker. And then you feel pretty confident afterwards and the patients are pretty satisfied. But again, this is something that when you're looking at a big group and you're saying it's statistically significantly improved, this does not apply to all patients, obviously. And it doesn't have the clinical significance.

Using anticholinergics or anti-muscarinics, again, we see a reduction in this one group of men, 31% reduction in nocturia over 12 weeks. In women, comparing two different cohorts, nocturia and severe OAB and those with nocturia with moderate OAB, and we could see that the improvement in reduction is better. But it also is improving relative to the severity as well. And I don't have a good explanation for that. But again, these are things that one would be monitoring, hopefully, with a voiding diary.

And even with some women you may want, because of the risk of assessment that you've done, you just want to make sure they're not retaining either. Diuretics are proposed often. And there's just these two small studies. 49 men with nocturnal polyuria using Furosemide six hours before bedtime and believe it or not, it only decreased the voids by 0.5 incidents. So really no help there. And even with the use of Bumetanide in the late afternoon, there were four less nocturia voids per week. That's a little hard to....

Nevertheless, in clinical practice, I'm sure all of you kind of do the same thing I do. If someone is already taking a diuretic, then I may just play around with the timing of the diuretic, like maybe 4:00 PM. But even when I do that, I feel so guilty, because I'm having somebody who has a social life and I'm impacting that, creating urinary frequency at the time that they may be meeting friends and going out to dinner. So again, these little things that we do, we have to be sensitive to our patients, something we can do with diuretics. But using diuretics like just de novo for this, probably not a good idea.

Then there's the rationale for the anti-diuretic hormone and that's Desmopressin. So this is a synthetic analog of ADH, the anti-diuretic hormone. It acts on the distal nephron and the collecting tubules to reduce salt and water excretion. So this grouping of 13 articles, all kind of corroborate the same conclusion, decreased nocturia, improved quality of sleep and extended first sleep. You'll see that a lot in the urological literature that's looking at using the anti-diuretic hormone. And I don't like that, because it's always making it seem like the first segment of sleep is somehow more important, and it's not. But it is a data point. In other studies, there is the concern for transient hyponatremia. But for the most part, there is this feeling that there is an efficacy. But again, looking at some of the raw data, what does that efficacy mean?

Less than a third of episodes of nocturia for men, less than 0.41 episodes of nocturia in men with the higher dose, with the 75 micrograms. And you get 40 minutes more of sleep before the first void. And in women, they get fewer voids, too. But again, we're talking these fractions. So what is statistical significance and how does this really apply to clinical satisfaction? And again, just reminding all of us about the importance of the sleep as I spoke about in the first lecture. The first half does have the deep sleep. But just because it's a deep sleep doesn't mean it's more important than the second half of sleep, where dreams occur. They're just as important and just have a different reason for the importance and value for our mental and physical health.

The good thing about using Vasopressin, and again, in the right patients, is that 90% of them will respond and stay on the medication, which means it's very well tolerated. Just in practical terms, I feel more comfortable using higher doses in men. Women have best responses. Thankfully, they only tolerate smaller doses. So that kind of works out well. It decreases the urine volume, increases sleep. Again, that's our goal. And in this series of articles, I found it interesting that the serious adverse effects that were associated with the trial didn't have anything to do with the medication. And in fact, when hyponatremia occurred, which ranged from 3 to 12%, it was rarely symptomatic.

So if someone were to use this, advise to start low. Monitor the sodium before, during and after the initial doses. Monitor for the adverse effects and titrate, if appropriate. And just as importantly, if after two to four weeks the patient is not responding, take them off the medication. And these are just some of the medications that should not be used in conjunction with Desmopressin, because it increases the risk of water intoxication and hyponatremia. So just take note of that. But again, the most important message is before using any pharmacological means as to treat the underlying cause, investigate the underlying cause and treat it.

When we consider the prevalence of undiagnosed sleep apnea, as I spoke about in the previous lecture, there is no pharmacological intervention that comes close to CPAP. I presented in an other lecture that CPAP in these patients led to a greater than two episodes per night decrease in nocturia. And as I just demonstrated, there is no pharmacological intervention that even comes close. So I'm trying to emphasize the importance of making the diagnosis of sleep apnea, and then really making a difference.

And perhaps this is data that may also help in enhancing compliance, helping patients understand why it's important that they could use the CPAP and that it really can be helpful. There are newer masks that are being used that are less intrusive. I mean, that's also an important issue for the partner. Sometimes the partners are greatly affected. They don't know what's worse, the snoring or the machines. But the machines have improved so much that that's no longer an argument.

So we have to find the underlying cause. And unfortunately, I got to tell a sad truth. There's usually more than one cause. So I'm just going to briefly review these cases. I have a 52-year-old man with acute onset of nocturia and I had a 65-year-old man with BPH and Parkinson's Disease, a 58-year-old woman with Multiple Sclerosis, with recurrent UTIs and nocturnal enuresis, and a 60-year-old man with BPH, a hundred ML PVR and he voids one to two ounces every hour, day and night.

So in the first man, the 52-year-old man, he has BPH. He's a weightlifter. So I was also worried about possible neurogenic bladder, some discogenic issues. But he also had new medications at the time that his NPi was greater than 0.33. Well, guess what? He was taking a calcium channel blocker in combination with the diuretic and he took it at bedtime. That was very easy to fix and it was so nice, but he was referred by a family doctor and they were thinking neurogenic bladder or something really ominous.

Here's the 65-year-old man, again, with BPH Parkinson's. This is a really double whammy. It's very hard to decide which part should take the priority. But he has bladder outlet obstruction. He does have urinary retention. He does have a neurogenic bladder. Urodynamics did prove he has detrusor hyperreflexia with impaired contractility. And he has an NPi of greater than 0.33. So with this person, we have to use multiple interventions. We have to treat the bladder outlet obstruction with the help of the neurologist. We have to find ways to better relax the bladder as well. And then also look at ways to diminish the NPi or improve the NPi. And with him, that means ruling out other things, like sleep apnea and cardiovascular insufficiency. But the Parkinson's, in and of itself, can also cause this. So then we really have to work at a lot of behavioral things and finding ways to help him compensate and get his sleep in other ways.

This really beautiful woman, she has such a complicated situation because obviously with MS, she has neurogenic bladder, she has features of spasticity and she also has retention. Her NPi is greater than 0.33. Now, her NPi is elevated. And again, that's really what's happening at night. She has a neurogenic bladder, but then she's challenged by this overflow of urine production caused by the neurological disorder and this autonomic dysfunction. During the day, however, she is severely dehydrated, because she doesn't want to wet herself. She's very social. She does a lot of volunteer work. And it's just really sad.

So in order to help her prevent her UTIs, we got to get her hydrated. And at the same time, it's impacting her marriage that she's wetting the bed at night, even though she is dehydrated. So very complicated case. And to make matters worse, a lot of our treatment options are limited, because she refuses to self cath. So that also makes it challenging.

And finally, this gentleman who had the high PVR, but he's voiding day and night. I mean, if you only saw his voiding diary in terms of time, you would think he has nocturnal polyuria. But in fact, his NPi was normal. And he actually did well after a TURP, which was very kind of scary because he's obstructed. He's got this high PVR. But these volumes are so small. And he did great, actually. But there is still the concern despite a neurological workup, is there something else that could be going on with him? But this has improved significantly. But again, the voiding diary helped a great deal.

So to understand the symptoms, understand and formulate the diagnosis, we have to listen, we have to examine. And we need that urinary diary. We can't just emphasize that enough. And just remember, it is a vicious cycle. There is a cause for nocturia. And nocturia causes serious problems, as well. And our goal is to have our patients wake up refreshed and, hopefully, healthier. So thank you.

Diane Newman: Thank you very much. I did not realize, you really taught me something about the fact of the drop in the number of episodes awakening at night to void with a CPAP versus all these medications, because you're right. We are so into, let's prescribe something, whether it be the alpha-blocker in combination with a anti-muscarinic or beta-3, without really thinking about outside the box. So it's a really good point. And here, I thought alpha-blockers were so impressive as far as successful and decreasing nocturia. But we're back to the fact that it's outside the bladder. It isn't it with the CPAP. So thank you. I mean, I didn't realize that data.

Jeannette Potts: You're welcome. And again, it's averages. As I said, I do like and select people combining the anti-muscarinic with the alpha-blocker and just doing some monitoring at first and then letting them go free. And they're fine until their annual follow-up. It's a tough thing. It's like, every time I look at something that's an average, well, that means that some people, and again, I hate to be so simplistic about it, but there's people who did very poorly on the treatment and people who did amazingly well. Well, I want to know about the amazingly well. What was it about them that they did amazingly well to make the average come out to be mediocre? Or as we saw, clinically insignificant.

Diane Newman: No, you're right. And we don't know those groups, because if we could identify that person that's going to do well with the medications, then you're right, it would really help us with treatment. The other thing though, I loved your case studies, because the first case study, I have to tell you, I had exactly the same case, it was actually a guy post-prostatectomy, a year later who had significant nocturia, which I just could not figure out. He was in his, I don't know, early 50s, a professional and I just couldn't. And literally, it was a combination of a new drug that had a diuretic, as well as an antihypertensive that he started taking at night. And it was so simple, you know what I mean? But it took me a little bit of time to figure out that's what it was.

And those cases are out there, whether it be a drug-to-drug interaction, or a new drug, the new onset because of a new drug, or whether it be chronicity of some other kind of condition that it really shows you that you need to look, again, beyond the bladder, or beyond the prostate in men, to figure out maybe what's the cause of that nocturia. And these other treatments, I do find behavioral does work in some people. The other thing that's getting a lot of press, very much so in the gray literature, is this sleep hygiene. And that the environment is so very important for sleep, because we talk about nocturia, but it is true that does the urge wake someone up or are they awake, because, I don't know, the room isn't very dark, or a noise or something?

And then when you're awake, what do they do? Oh, I feel like I need to go to the bathroom, so I'll go to the bathroom. So that is always, to me, difficult when I talk to patients, is it true nocturia, because of the bladder? Or is it because they're awake, because they're poor sleepers?

Jeannette Potts: Yeah. Yeah. It's hard to tell.

Diane Newman: It's really hard to tell. Well, thank you very much. This is three different lectures on nocturia. And we really thank Dr. Potts for giving us some really, things that we can use in clinical practice, but also giving that background as far as the evidence base as far as where we are with nocturia treatment. So thank you very much.

Jeannette Potts: Thank you.