Noctiva for Nocturia: are we treating the symptom and not the cause?

You may have heard a new drug has been approved to treat the problem of nocturia (those middle of the night urges that lead men and women to leave the bed and visit the bathroom to urinate). As covered by many news outlets in March of this year, the new drug Noctiva is based on an old formula of the drug desmopressin that was originally developed for people with low levels of the body’s natural hormone vasopressin. Vasopressin, also known as antidiuretic hormone or ADH, obviously acts opposite of a diuretic, that is, it influences the kidneys to conserve water, which should decrease urination any time of day or night. As you might imagine if you become dehydrated for some reason, then ADH should be activated in the bloodstream to prevent your kidneys from passing too much fluid, which would help to stabilize your blood pressure. Without the secretion of ADH, you dehydration might lead to a serious bout of hypotension (low blood pressure) and eventually a state of shock, a life-threatening drop in blood pressure.

In summary, when someone receives desmopressin the kidneys conserve more water and thus decrease the urgency to head to the bathroom in the middle of the night. Enter Noctiva, a new pharmaceutical formulation for the treatment of nocturia; as a variation of desmopressin it sounds like a useful way to decrease nocturia episodes, which unequivocally is a serious condition in the elderly where it serves as a leading cause of falls, broken hips, and ultimately mortality. Nocturia is also a serious condition for chronic insomniacs where the minutes spent transiting back and forth to bed plus the time spent at the toilet often proves sufficient to fully awaken individuals, after which insomniacs’ tendencies toward racing thoughts lead to new rounds of unwanted sleeplessness. Thus, a strong case can be made for the potential value of the drug.

However, as we described many years ago, nocturia is often a core component of the pathophysiological effects of obstructive sleep apnea (OSA) and upper airway resistance syndrome (UARS). As we explained in this video, the biological effects of OSA and UARS specifically trigger a natural diuretic (atrial natriuretic peptide) in a chamber of the heart to be released into the bloodstream, which in turn leads the kidneys to produce more urine and eventually more trips to the bathroom. This mechanism is so-well researched and documented in the scientific literature and yet flies so far under the radar that nearly all urologists know nothing about it and even the vast majority of primary care physicians remain in the dark.

I trust you see where this post is headed. If someone invents or discovers a drug to treat nocturia, then how many patients with these problematic trips to the bathroom would never receive a thorough sleep evaluation to test for a more likely cause of the condition, namely OSA and UARS? Equally troubling, a recent issue of the Journal of the American Medical Association included a commentary on the general dangers of overuse of this new medication, because of its specific approach to symptomatic relief instead of searching to find the cause. Yet, this otherwise excellent commentary makes no mention of the connection between OSA and nocturia, missing out on an important opportunity for exposure in a major scientific journal.

Disappointed in the commentary for the absence of sleep-related issues, I sent the following email to the author: “I am curious to know why there was no mention of the well-described connection between sleep apnea and nocturia in your otherwise excellent JAMA commentary. I presume you are familiar with the pathophysiology of atrial natriuretic peptide release in OSA patients. If not, please see my short video on the topic at www.nocturiacures.com. Nocturia is one of the most frequent presenting complaints in OSA patients, as frequent as snoring: see Romero E, Krakow B, Haynes P, Ulibarri V. Nocturia and snoring: predictive symptoms for obstructive sleep apnea. Sleep Breath. 2010 Dec;14(4):337-43. doi: 10.1007/s11325-009-0310-2. Epub 2009 Oct 29. Thus, our field of sleep medicine has great concern that isolated treatment of nocturia will dissuade patients from seeking referrals to sleep medical centers where comprehensive treatment with positive airway pressure therapy almost invariably leads to decreased nocturia episodes and a complete resolution of the problem in 50% or greater of cases.”

These types of “sleep-less” commentaries occur frequently in the scientific literature on the topic of nocturia, that is, they omit more often than not any meaningful acknowledgment or discussion about OSA and nocturia. None of these editorial approaches are going to change any time soon, because it takes a long time for new information to wend its way into being established as the new “conventional wisdom.” Looking at two relatively recent articles published on the topic of nocturia will give you an idea of how long things take.

The first article was published last year and describes a group of individuals less than 50 years old who were diagnosed with OSA and planned on starting CPAP therapy.1 Unsurprisingly, the study showed that many of these patients reported nocturia, and nocturia decreased in 85% of the patients using CPAP. Such an article should be an earth-shattering wake-up call, because the study comprised a younger cohort of men who by age alone would not be expected to suffer a high prevalence of urologic conditions. Yet, 85% experienced improvement in nocturia just by using CPAP. Any primary care physician should jump all over this data and start referring all their younger male patients with nocturia and normal prostate exams to complete sleep testing, but in reality 10 or 20 of the same studies will need to be conducted before we see the transformation of care to this more comprehensive level.

The second article is even more dramatic because it occurred within a population of patients visiting a urology clinic.2 Here, the authors found 70% of patients seeking treatment at a urology clinic for nocturia actually had OSA. They also reported some patients had already attempted and failed conventional urological treatments and thereafter succeeded in decreasing nocturia with the use of CPAP. Even more telling is their final comment in the Conclusions of the Abstract: “Patients who complain of nocturia must be assessed for SDB [sleep-disordered breathing] before starting therapy for nocturia” [italics added]. Can you imagine how and to what extent things would change in urology clinics around the world if instead of using medications or surgical interventions, all their patients underwent sleep testing first as recommended? At minimum, can you imagine the tremendous economic disruption in the field of urology as greater than 50% of patients (per this study) would likely solve their problem with CPAP? Again, this scientifically-validated approach will not find its way into mainstream practices until the study concepts are repeated another 10 to 20 times in 10 to 20 different urology clinics. Even then, territorial anxieties and fears will prevent the bulk of urologists from rushing headlong into supporting, advocating and practicing in accord with this evidence, because it is difficult mentally, emotionally, and financially for any physician to cope with dramatic changes in the manner in which they should be practicing in his or her field.

Still, this post does not seek to condemn the use of Noctiva in appropriate patients, which could even turn out to be OSA/UARS cases where PAP therapy is impractical or simply impossible to use. Given the disappointing adherence rates described in the sleep literature, it is not difficult to build a case for the use of Noctiva in failed PAP therapy cases. Nonetheless, my major concern is that many of these cases will never be diagnosed because some healthcare provider will recommend Noctiva before recommending a sleep evaluation.

The release of the drug is very recent so there is no evidence to report on at this point, but close monitoring of the dispensing of Noctiva is certainly in order. And for sleep medical professionals, who have the capacity to educate primary care physicians as well as urologists, it is imperative to follow these trends, because in all probability we will start seeing patients arriving at our centers already prescribed the drug. When these encounters arise, it will present prime opportunities for educating primary physicians, urologists and most importantly patients.

Closing on a positive note, the author of the JAMA commentary emailed me back and was very interested in our work cited above (published in Sleep & Breathing) and the nocturia video. He reported finding the new perspective useful and anticipated being able to incorporate these ideas in future work. So, it is useful to communicate with our colleagues; medical knowledge is already vast and continues to grow exponentially. As sleep doctors we must work diligently to help other medical professionals appreciate the importance of sleep and its disorders.

References

1

Maeda T, Fukunaga K, Nagata H, Haraguchi M, Kikuchi E, Miyajima A, Yamasawa W, Shirahama R, Narita M, Betsuyaku T, Asano K, Oya M. Obstructive sleep apnea syndrome should be considered as a cause of nocturia in younger patients without other voiding symptoms.Can Urol Assoc J. 2016 Jul-Aug;10(7-8):E241-E245. doi: 10.5489/cuaj.3508. Epub 2016 Jul 12.

2

Yamamoto U, Nishizaka M, Yoshimura C, Kawagoe N, Hayashi A, Kadokami T, Ando S. Prevalence of Sleep Disordered Breathing among Patients with Nocturia at a Urology Clinic. Intern Med. 2016;55(8):901-5. doi: 10.2169/internalmedicine.55.5769. Epub 2016 Apr 15.

About the author

Image of Dr Barry Krakow, sleep physician and HST America blog contributor.

Dr Barry Krakow’s 27 years of sleep research have focused on the complex relationship between physiological and psychological sleep disorders. Dr. Krakow started in sleep research in 1988 and helped pioneer innovative therapies for chronic nightmare patients. Since 1995, he has practiced sleep medicine full-time and currently operates Maimonides Sleep Arts & Sciences, Ltd., a private sleep medical center specializing in the treatment of sleep disorders such as insomnia and sleep apnea in mental health patients. He is also principal investigator of the Sleep & Human Health Institute, a non-profit research center that focuses on the complex interplay between physiological and psychological sleep disorders.

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