Nocturia: Finding an Identity

Case Review Nocturia: Finding an Identity Benjamin M. Brucker, MD NYU Langone Health, New York, NY Nocturia is a condition that has a tremendous impact on a patient’s health and well­ being. Getting up 2 or more times a night to urinate fragments sleep, preventing deep, restorative stages of the sleep cycle. With safer and more effective therapies, nocturia is a treatable condition that no longer should be overlooked. The simplicity of directly targeting the cause of nocturia, the overproduction of urine (ie, nocturnal polyuria) should be considered. Noctiva™ (desmopressin acetate) nasal spray (Avadel Pharmaceuticals plc, Chesterfield, MO), a novel FDA-approved microdose desmopressin nasal spray, can reduce nighttime urine production and potentially mitigate the potential harm of nocturia. [Rev Urol. 2018;20(4):170–173 doi: 10.3909/riu0822] ® © 2019 MedReviews , LLC KEY WORDS LUTS • Nocturia • BPH • Desmopressin acetate • Quality of life N octuria is highly prevalent, and undeniably has a negative impact on sleep and healthrelated quality of life. However, urologists still debate if it is a symptom or if it is a stand-alone condition. Perhaps we need to accept that nocturia can be both. “Nocturia” exists as a symptom of several conditions that affect the lower urinary tract. As a symptom of benign prostatic hypertrophy (BPH), nocturia can result in profound bother. Similarly, in a patient with overactive bladder (OAB), the nighttime voids (nocturia) lead to significant impact on quality of life. However, some patients have the chief complaint of nocturia, and overlooked is the opportunity to consider that nocturia is a condition worthy of addressing. Case Report History A 67-year-old man presented with a chief complaint of “getting up at night to urinate.” He noted that he is getting up 3 to 4 times a night. He had no trouble falling back to sleep, but he said that when he wakes up in the morning, he does not think that he has had a good night’s sleep. His wife, who joined him for his doctor’s visits, is also disturbed by the frequent interruptions at night. She noted that he seems grumpy and irritable and thinks that his lack of deep sleep is the problem. She said that he does not snore. He stated that he voids about 6 times during waking hours. He thinks that when he urinates 170 • Vol. 20 No. 4 • 2018 • Reviews in Urology 4170018_00_RIU0822_V4_rev04.indd 170 1/21/19 7:26 PM Nocturia: Finding an Identity at night, the volume he voids is about the same as what triggers a daytime voiding event. He had not noticed any improvement in his nocturia with alterations in fluid consumption prior to going to bed. He had significant lower urinary tract symptoms (LUTS) a few years ago (slow stream, urgency of urination, and nocturia) and, after only a mild improvement with an alpha-blocker, he underwent a photoselective vaporization of the prostate (PVP) about 3 years earlier. He was very happy with the improvement in his urinary flow, and no longer has urinary urgency. He stated he was hoping the nighttime symptoms would have improved with the PVP, as he recalls the nighttime component was perhaps the most bothersome symptom, but this has persisted. Past Medical/Surgical History The patient’s past medical history was positive for seasonal allergies (utilized oral antihistamines as needed) and mild hypertension (well controlled with a calcium channel blocker). He indicated that his past surgical history includes a repair of a torn ligament in his left knee and excision of a lipoma on his back. Physical Examination • Blood pressure, 128/80 • Heart rate, 75 • Respiratory rate, 12 • Body mass index (BMI), 26 • Temperature, 98.8 On examination, the patient is reasonably fit, but appears tired and mildly disheveled. He has a normal genital examination and his prostate feels smooth and benign, but large. He has no significant lower extremity edema. His abdomen is soft and non-tender. Additional Testing • Urine analysis, dipstick negative • Basic metabolic panel (BMP)  Serum sodium, 142 Serum creatinine, 1.1 • Noninvasive flow   Qmax, 20  Q average, 15  Voided volume, 250 mL Post-void residual volume (PVR), 50 mL • Bladder diary   24-hour bladder diary shows that more than 45% of the patient’s 24-hour urine production is made at night (this nighttime urine production includes 3 nocturia episodes and the first morning void). This volume of nighttime urine production (defined in adults as .33%) indicates that his nocturia is caused by nocturnal polyuria (NP). Treatment Careful history showed that the patient does not consume an excessive amount of fluid in the evenings. The diary is notable for an absence of significant bladder irritants prior to bed time. He has attempted changes to his sleep and bedtime routine to help the extreme fatigue, but these have not proven successful. His urinary flow and PVR do not suggest any significant bladder outlet obstruction (BOO); and show an improvement from his evaluation prior to the PVP 3 years earlier. He is complaining of nocturia, and it is impacting him and his wife. After establishing a baseline serum sodium level and ensuring no significant renal function impairment, he was started on one spray of Noctiva™ (desmopressin acetate) nasal spray (Avadel Pharmaceuticals plc, Chesterfield, MO), 0.83 mcg. This dose was selected based on his age ($65 years) per the prescribing information.1 This is used in one nostril, once a night, just before bed. The patient returned for a follow-up visit after a week of therapy. At this visit he reported that he is now usually not getting up at all, or on some occasions might get up once a night. He has already noticed that daytime concentration has improved. His serum sodium is checked, and this is unchanged from baseline. He stays on Noctiva, 0.83 mcg, and at 1 month he and his wife note a substantial improvement in energy, daytime function, and mood. Discussion This patient and his wife were feeling the effects of chronic sleep deprivation. There was clearly an impact on daytime function due to sleep interruption. The International Continence Society defines nocturia as the complaint that the individual must wake at night 1 or more times to void.2 This defines a nocturic episode, but multiple studies have shown the negative impact of nocturia when individuals wake up 2 or more times a night on quality of life and the contribution to impaired sleep and overall health.3,4 Even with this higher threshold for defining nocturia (ie, 2 or more episodes), the number of patients affected by nocturia is tremendous. The incidence of waking 2 or more times to void is about 30% in men and women age 60 to 69 years.5 Nocturia is the leading cause of sleep disturbance in patients older than 50 years, places elderly patients at risk of falling, and has even been associated with increased mortality.6,7 Our patient had been treated previously for LUTS (which included Vol. 20 No. 4 • 2018 • Reviews in Urology • 171 4170018_00_RIU0822_V4_rev04.indd 171 1/21/19 7:26 PM Nocturia: Finding an Identity continued the complaint of nocturia). His LUTS were first treated with an alpha-blocker, and then with an outlet reduction procedure. He had demonstrated obstructive voiding complaints and this was a reasonable approach. His symptoms did improve; however, we should not be surprised that he was still suffering from nocutria, based on available data. Nocturia is caused by nocturnal polyuria in 88% of patients.8 He noted that his voids are normal volume and thus even without a bladder diary the suspicion for nocturnal polyuria is very high. Alpha-blockers are not going to address the overproduction of urine, thus the improvement that is seen with that therapy is modest at best. Pooled data from three studies looking at alfuzosin, 10 mg, showed a statistically significant improvement in nocturia; however, the clinical change is very small, close to that of placebo (an absolute reduction of 21.1 void per night with alpha-blocker vs 2 0.8 with placebo).9 Similarly, a small effect was seen in a cohort study of men with BPH and nocturia.10 In this study, tamsulosin reduced the number of episodes of nocturia in 17.9% of men and transurethral resection of the prostate (TURP) reduced episodes in 32.2% of patients. However, the degree of improvement was lowest among the individual symptoms measured. The reduction was one-half point for the medication group, and just 1 point for the surgery group. In this case, the patient was complaining of nocturia, which may have been considered a symptom in his past, but now clearly needs to be considered as a condition that should be addressed. A safe and effective treatment is now available. Desmopressin acetate nasal spray was approved by the US Food and Drug Administration in 2017 for the treatment of nocturia due to nocturnal polyuria in adults who awaken at least twice nightly. In clinical trials, Noctiva reduced nocturnal voids by $50% in up to 49% of patients.11 The threshold of 50% reduction in nocturic episodes is very high, considering that even a more modest improvement may be clinically meaningful. Therefore, the number of patients that would gain clinical benefit is much higher. Given the large size of the registration trials, we have meaningful data in multiple subpopulations of patients with nocturia for Noctiva. Looking specifically at patients with nocturia and BPH, 30% to 37% achieved a $50% reduction in nocturic episodes per night after treatment with the 0.83 and 1.66 mcg Noctiva dose, respectively. Patients with BPH and nocturia experience 1.3 or 1.4 fewer nocturic episodes/ night with Noctiva treatment (0.83 mcg and 1.66 mcg, respectively). This was a significant improvement compared with placebo.12 Another measure that may explain the profound impact of Noctiva on nocturia is the improvement in first uninterrupted sleep (FUSP). In the overall population, patients in the treatment arm with either microdose of Noctiva (0.83 mcg or 1.66 mcg) were able to achieve 4 hours of uninterrupted sleep.13 Presumably, the ability to improve deep, restorative sleep in the early part of the night is why improvements in quality of life are seen. Noctiva allows for the lowest possible dose of desmopressin acetate to be consistently delivered night after night. It utilizes a permeation enhancer (cyclopentadecanolide) and an engineered spray pattern that promotes rapid absorption, and then relies on predictable metabolism of the drug to limit activity of the desmopressin acetate to the time when the patient is asleep. This means that the incidence (and worry) of significant hyponatremia is very low. In fact, with more than 1000 patients, the overall incidence of severely low serum sodium (#125 mmol/L) was 0.7%.13 This extremely low incidence was Main Points • Benign prostatic hyperplasia, overactive bladder, and nocturia are conditions that overlap, coexist, and share symptoms. • Nocturia has a tremendous impact on a patient’s health and wellbeing. Getting up two or more times a night to urinate fragments sleep, preventing deep, restorative stages of the sleep cycle. • Desmopressin acetate nasal spray was approved by the US Food and Drug Administration in 2017 for the treatment of nocturia due to nocturnal polyuria in adults who awaken at least twice nightly. In clinical trials, Noctiva reduced nocturnal voids by $50% in up to 49% of patients. • It is imperative to consider that nocturia, at times a symptom, is very often a condition that deserves its own directed therapies. 172 • Vol. 20 No. 4 • 2018 • Reviews in Urology 4170018_00_RIU0822_V4_rev04.indd 172 1/21/19 7:26 PM Nocturia: Finding an Identity seen in a population that were not instructed to restrict fluids, and had about 50% of patients over the age of 65 years. Hyponatremia can have serious consequences if unrecognized, so routine monitoring is good practice. The recommendations are to ensure a normal serum sodium level prior to initiation of treatment, within 1 week of starting therapy with Noctiva, at 1 month, and then periodically as clinically indicated. More frequent checks can be utilized in patients at high risk for electrolyte imbalances or hyponatremia. Conclusions Nocturia seems to puzzle urologists because it can be a symptom of BPH, but it also can be a condition that coexists with BPH. Consider a similar scenario with the symptom of urinary “urgency.” Urgency is the defining symptom of OAB, essentially making urgency a standalone condition. After a thorough history and basic examination, most clinicians feel comfortable using a medication (ie, anticholinergic or beta-3 agonist) to treat OAB and the associated urgency. Usually, no disease-specific testing is needed. We treat urgency, diagnosed clinically and given a name of OAB. We treat the complaint with a drug targeting the presumed mechanism for the urgency, involuntary bladder contractions. In some cases, urgency exists in a man with BOO secondary to BPH. If the man is bothered by a slow stream, has an enlarged prostate on examination, even if he has urgency and urgency incontinence, we often address the obstruction first. The difference here is once the outlet has been treated, it is common for us to assess if urgency is persisting. When urgency remains, we quickly add a therapy (ie, anticholenergic, beta-3 agonist, phosphodiesterase type 5 inhibitor) to relieve the symptom of urgency. In fact, that patient maybe labeled as having a persistence of his OAB symptoms, even though he was clearly labeled with the condition of BPH. We easily reclassify the patient as OAB, perhaps because it is a wellrecognized condition. In this case, involving a patient with BPH treated for BOO (but with persistent symptoms), we have not thought of nocturia in the same way. If the persisting symptom is nocturia (and not urgency) we are less inclined to reclassify or intervene. OAB, BPH, and nocturia are conditions that overlap, coexist, and share symptoms. We look to classify patients with unique conditions before we start treatments. It is imperative to consider that nocturia, though at times a symptom, is very often a condition that deserves its own directed therapies. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. NOCTIVA [prescribing information]. Chesterfield, MO: Avadel Specialty Pharmaceuticals, LLC. March 2017. Van Kerrebroeck P. Abrams P, Chaikin D, et al. The standardisation of terminology in nocturia: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn. 2002;21:179-183. DuBeau CE, Yalla SV, Resnick NM. Implications of the most bothersome prostatism symptom for clinical care and outcomes research. J Am Geriatr Soc. 1995;43:985-992. Tikkinen KA, Johnson TM, Tammela TLJ, et al. 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Dr. Brucker is a Consultant Speaker for Avadel Pharmaceuticals, a Consultant for Serenity and Watkin-Conti, and Advisor and an Investigator for Allergan and ISPEN. Vol. 20 No. 4 • 2018 • Reviews in Urology • 173 4170018_00_RIU0822_V4_rev04.indd 173 1/21/19 7:26 PM