Ask the Experts – Alan J Wein

Ask the Experts
Nocturia: ‘A Legitimate Stand-Alone Problem’

Alan J. Wein, MD

Practice Community
Philadelphia, PA

Hospital and Institutional Affiliations
Founders Professor and Emeritus Chief of Urology, Co-Director of the Urologic Oncology Program, and Co-Director of the Voiding Function and Dysfunction Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
Number of Patients Seen in a Week

Practice Niche
Voiding Function & Dysfunction Urologic Oncology

Question 1. Is there a take home message from the various presentations at this year’s AUA annual meeting?
The main message coming out of the meeting is that nocturia is a legitimate stand-alone problem that is associated with a number of negative things, such as increased mortality, increased falls and fractures, depression, increased sleepiness during the day, decreased attention to work, increased number of sick days, which may or may not be cause and effect. You’ll never really know that until you fix the nocturia to see if they go away. Nocturia is the most common urinary tract symptom. With men who have bladder outlet obstruction secondary to prostatic enlargement, it’s also the thing that bothers them the most. If you look at the totality of people who have lower urinary tract symptoms, the minority have urinary incontinence; the majority have some element of nocturia.
Question 2.  One of the studies presented at this year’s AUA annual meeting (Drangsholt S et al. Poster MP27-14) concluded that nocturia treatment is modest at best. What are your thoughts?
Medications used to treat people with overactive bladder (OAB) and benign prostatic hyperplasia (BPH) have little effect on nocturia. If you have patients who have OAB, which is urgency with or without incontinence, and usually with frequency and nocturia, and you treat those people with OAB medications, then you’ll improve their frequency by about 20%, you’ll improve their urinary incontinence episodes—if they have urgency incontinence—anywhere from 40% to 70%, and you’ll improve their urgency episodes by 25% to 50%. But you won’t have much of an effect on their nocturia. At best, if they get up 3 times a night, you’ll decrease their nocturia to 2, 2.5 episodes a night, but only if they have severe urgency associated with their waking to void. Meta-analyses looking at the effect of antimuscarinics and nocturia show that the difference between drugs and placebo was 0.2. So at best there is a modest effect of OAB drugs on nocturia. If you look at the individual studies, that’s really what the difference is. In some studies, there is no difference at all. The situation applies to medications for BPH. The placebo effect in nocturia is extraordinarily high. The lowest I’ve ever seen is 20%, the highest, 40% to 50%. People in a study may unconsciously reduce their fluid intake so that their overnight urine output is decreased even though they were not on the OAB drug.

Now there’s an FDA approved medication in the US (Noctiva, formerly AV002) to treat nocturia that’s due to nocturnal polyuria—50% of people get 50% better. Within that population who gets better, everything improves. First uninterrupted sleep period is lengthened past 4 hours, which is sort of the magic number according to the sleep experts. They get up fewer total times a night. Quality of life gets better. You can use it in people who do or don’t have overactive bladder or BPH.
Question 3. When should doctors prescribe the new drug?
Let’s say a 65-year-old man comes to the office complaining of hesitancy, decreased stream, and urgency, and he says the daytime symptoms don’t bother him, but the nighttime urination, getting up 4, 5 times a night, is a major problem for him. In these cases, I think the drug can be used first line. But if the man says all the urinary symptoms bother him, he urinates 9 or 10 times a day, his stream is poor and he gets up frequently at night to urinate, the average urologist most likely would treat him for BPH, so they would give him an alpha blocker or a 5-alpha-reductase inhibitor. If the man comes back and says he’s actually doing a lot better during the day but still gets up 3 times a night, then the new drug can be used as second-line therapy while continuing first-line therapy. So I think the drug will be used as both first-line and second-line therapy depending on the severity of complaints.
Question 4. What are some other ways to manage nocturia?
There are a lot of quick hits that physician can do for somebody who has nocturia. One such quick hit is to have patients with congestive heart failure lie down for an hour, hour and a half, at about 4 o’clock in the afternoon. With congestive heart failure, fluid is retained outside of the vascular system. When patients lie down at night, all this accumulated fluid enters the vascular system, increasing blood pressure and renal blood flow, which increases the amount of urine produced. If patients lie down in the late afternoon, a lot of that fluid returns to the vascular system. That fluid is urinated out before they go to sleep at night. The number of times during a 24-hour period that they urinate doesn’t change, but the urination distribution changes, so they do it more when they’re awake when it’s less bothersome than when they go to bed and try to go to sleep, when it becomes more bothersome. This works for anyone with lower extremity lymphedema. Sleep apnea is a quick hit, as is better control of diabetes and hypertension..
Question 5. What underlying causes of nocturia are underappreciated?
The most startling cause is sleep apnea. Doctors just don’t think to ask patients about sleep apnea when they complain about nocturia. Sleep apnea causes hypoxia, resulting in pulmonary vasoconstriction. This leads to increased right atrial pressure that stimulates secretion of atrial natriuretic peptide, which then causes release of arginine vasopressin. If you give patients a CPAP mask, and the patient uses it successfully, it’ll improve the nocturia right away, the first night.
Question 6. Are there areas of nocturia research that need more attention?
One unexplored clinical question is whether antidiuretic drugs work as well in patients who do not have nocturnal polyuria. One of the definitions of nocturnal polyuria is the output of 33% of 24-hour urine production at night. Suppose somebody makes a lot of urine during the day, but less than 33% of their urine output at night. Does the drug work less well in those patients, and, if so, how much less?

Another area that needs to be explored is whether the negative associations with nocturia, such as increased falls and fractures, cardiac disease, and increased mortality are the cause or result of nocturia. The only way you can prove that is to measure the incidence of those negative associations in a large cohort of patients whose nocturia had been treated successfully and then compare that incidence with the incidence before they were treated. Do those negative associations go away when you successfully treat nocturia?

Suggested Readings

1. Brucker BM, Francis L, Yang, Rovner ES. Extended first uninterrupted sleep period in elderly patients following treatment with AV002, an emulsified low dose vasopressin analog for nocturia. Data presented at the American Urological Association 2018 annual meeting, San Francisco, May 18-21. LBA12.

2. Freedland S, Howard L, Bliwise D, et al. Nocturia is associated with increased risk of death: Results from REDUCE. Presented at the American Urological Association’s 2018 annual meeting in San Francisco, May 18-21. Poster MP04-15.

3. Drangsholt S, Slawin J, and Brucker B. Clinical evaluation and treatment of nocturia is modest at best. Presented at the American Urological Association’s 2018 annual meeting in San Francisco, May 18-21. Poster MP27-14.