In this key opinion leader (KOL) interview, Herbert Lepor, MD, Medical Editor of Reviews in Urology, and Roger R. Dmochowski, MD, Professor, Department of Urologic Surgery at Vanderbilt University, discuss management options for nocturia.
Dr. Lepor: Thank you for joining me today. Tell me, what is the definition of nocturia and what is its incidence in the population?
Dr. Dmochowski: The strict definition of nocturia, or arising from sleep to urinate, is any occurrence of this event that disturbs sleep. Bothersome nocturia usually occurs when two or more nocturic events occur per night. Usually nocturia is defined as a urinary event that has occurred after a period of initial sleep and is followed by an attempt to return to sleep. As it is emphasized by this definition, abnormalities of sleep may clearly impact an individual’s ability to fall asleep initially or to return to sleep after being awoken by the need to void. However, as with all the things pertaining to lower urinary tract symptoms (LUTS), bother is experienced differently by different individuals. Some younger individuals are greatly bothered by a single event of nocturia, whereas some relatively older individuals tend to not be bothered until the frequency of nocturia increases to three or four times a night.
The incidence of nocturia increases with age and some studies have noted as many as 30% of unique populations over the age of 60 being impacted by this condition. Incidence is contingent upon criteria used to define the condition, meaning that the overall occurrence of nocturia is more significant if a single event per night is used for the definition versus those studies that use a greater occurrence for the definition. Whichever definition is chosen, this condition is very common and often very impactful to a variety of issues related to an individual’s daytime cognitive and emotional status and the quality of sleep that the individual can attain.
Dr. Lepor: What are the causes of nocturia?
Dr. Dmochowski: Nocturia has multiple co-morbid conditions and underlying pathophysiologies associated with the symptom complex. One of the most common associations and causes of nocturia, getting up at night to urinate, is nocturnal polyuria, or the over-excretion of urine occurring during the night-time hours. Some studies place the frequency of nocturnal polyuria in the nocturic population at 80% or more. Nocturia is often associated with other LUTS complexes including benign prostatic hyperplasia (BPH) and overactive bladder (OAB). Some patients experience nocturia due to diminished night-time bladder capacity, although this is less common. It is important to note the association of nocturia with other significant comorbidities that affect homeostasis of fluid in the human body. An extremely common association is that with sleep apnea, which impacts right heart and pulmonary function.
Dr. Lepor: What is an appropriate evaluation for nocturia: history, laboratory testing, and other diagnostic studies?
Dr. Dmochowski: An appropriate evaluation includes elements from all three factors. Historical factors of interest include nocturia duration and magnitude (number of episodes) that are experienced by the individual. Often these patients have experienced symptoms for years and assume that the condition is a natural part of aging and one for which no real treatment exists. Of importance, a medical history is critical to obtain including the presence of sleep apnea, any diagnosed cardiopulmonary conditions, any signs of recurrent floor extremity edema, and any presence of sleep-cycle disturbance. All these conditions are potentially contributory to the condition of nocturia. Additionally, medications contributory to this condition include diuretics (especially short-acting diuretics taken before sleep), some anti-depressant medications, and even lithium. A voiding diary with an emphasis on night-time urinary volume and nocturic episodes is important to delineate the amount of urine produced while asleep for purposes of identifying the patient with nocturnal polyuria. Ancillary tests that may be of value include urinalysis, post-void residual volume, and consideration of non-urologic testing and referral (such as sleep studies when apnea is suspected).
Dr. Lepor: Nocturia is often associated with LUTS/BPH and OAB. How effective are drugs at relieving nocturia in patients with BPH and OAB?
Dr. Dmochowski: The relative effectiveness of drugs used for BPH and OAB for nocturia improvement is marginal at best. Historically, agents for these conditions have been used to ameliorate symptoms of nocturia assumed to be coexistent with either BPH or OAB. Evidence reviews have demonstrated class effects of reductions of less than one nocturic episode per night with either anti-muscarinics or alpha agents. The overall magnitude of effect, therefore, is marginal.
Of importance, there are behavioral interventions that have been described that have similar levels of efficacy, such as night-time volume intake reduction, sleep hygiene improvement, afternoon leg elevation (to re-centralize peripheral edema), and timing change for diuretic ingestion.
Dr. Lepor: What do you think of the concept of decreasing nocturnal urine production during the night as a strategy for treating nocturia?
Dr. Dmochowski: This strategy is a cornerstone for the treatment of nocturia that results from nocturnal polyuria. Although the number of patients with nocturnal polyuria varies between nocturia studies, it can be roughly assumed that most patients with nocturia do have nocturnal polyuria. Recent studies have demonstrated that approximately 80% of patients with nocturia have concomitant nocturnal polyuria as a contributing component to their nocturic syndrome. By reducing urine presented to the bladder, the overall volume of urine to be voided necessarily is decreased, thereby benefiting the patient with nocturia.
Dr. Lepor: Should the first step be behavior modification?
Dr. Dmochowski: Yes, it should. The interventions mentioned earlier—nighttime volume intake reduction, sleep hygiene improvement, afternoon leg elevation (to re-centralize peripheral edema), and timing change for diuretic ingestion—may provide certain levels of demonstrable benefit for the unique individual and therefore should initially be considered as a starting point for any subsequent therapy. Often, behavioral management also serves to focus the patient on their condition and provides educational, therapeutic, and motivational value.
Dr. Lepor: Does desmopressin acetate decrease nocturnal urine production? If so, why isn’t this drug used more commonly for treating nocturia?
Dr. Dmochowski: Desmopressin acetate does decrease nocturnal urine production by mimicking naturally occurring arginine vasopressin activity at the level of the renal tubules, resulting in avid reabsorption of fluid from the filtrate prior to its deposition in the bladder. The reason desmopressin acetate has not been used more commonly for the treatment of this condition is the risk of hyponatremia associated with older formulations of the compound. This risk of hyponatremia is real and, especially with the older formulations, has resulted in symptomatic hyponatremia requiring medical intervention and even hospitalization. Older formulations have been produced in both oral and nasal spray formulations and have been used for childhood bedwetting and for hematologic indications.
Dr. Lepor: Noctiva™ (desmopressin acetate) nasal spray (Avadel Pharmaceuticals plc, Chesterfield, MO) was recently US Food and Drug Administration–approved for the treatment of nocturnal polyuria. What is unique about this drug? Do you have to worry about hyponatremia?
Dr. Dmochowski: This formulation utilizes a nasal delivery system with a unique application of active agent to the nasal mucosa by a plume spray, accompanied by a permeation enhancer that allows rapid absorption and predictable serum levels associated with relatively short half-life and relatively high bioavailability. The predictable bioavailability and demonstrable short half-life reduce the risk of hyponatremia while providing efficacy during the discreet time of active compound circulation.
Dr. Lepor: Are there contraindications for using Noctiva?
Dr. Dmochowski: There are contraindications to the use of this agent, which include polydipsia, glomerular filtration rate of less than 50 mL/min, syndrome of inappropriate antidiuretic hormone secretion (SIADH), illnesses associated with fluid or electrolyte imbalance (emesis or persistent diarrhea), congestive heart failure (New York Heart Association Class II-IV), uncontrolled hypertension, concomitant use of systemic corticosteroids, concomitant use of loop diuretics, individual history of current or historic hyponatremia, and primary nocturnal enuresis. All these conditions should be considered and are aspects of the patient history that should be obtained.
Dr. Lepor: How effective will Noctiva be in patients without nocturnal polyuria?
Dr. Dmochowski: The agent is most effective for reduction of urine volume and therefore shows most benefit for nocturnal polyuria. However, it should be remembered that nocturic frequency is caused by urine volume and therefore even patients without polyuria may derive some benefit from the formulation.