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Protocol for a randomized, double blind, placebo controlled, crossover trial of Melatonin for treatment of Nocturia in adults with Multiple Sclerosis (MeNiMS)

Delgado D, Canham L, Cotterill N et al.

BMC Neurology 2017; 17:63

Commentary by Don Bliwise:
This paper describes in exquisite detail the experimental protocol for an intended randomized clinical trial (RCT) of melatonin for the treatment of nocturia in multiple sclerosis (MS). There are several noteworthy aspects regarding this RCT. First, it is not industry sponsored (which may not be altogether surprising since melatonin is a dietary supplement and is freely available in most countries in the world) and is instead sponsored by a MS patient group in the United Kingdom. Second, the design is formidable and consists of 2 6-week treatment phases delivered in a crossover design separated by a 1 month wash out, always a desirable feature in a crossover trial. Third, other aspects of the trial design, including inclusion/exclusion criteria, specification of primary and secondary outcomes, and statistical power calculations to project sample size, are all well presented. In fact, for researchers wanting a good template for the design of any potential pharmacologic treatment for nocturia, this paper represents a nice model of how one might design such a trial.

Commentary: Melatonin is a particularly provocative choice of medication to select in a nocturia trial for many reasons. In humans, endogenous melatonin is often thought of as a “’sleep hormone,” when it is much more accurately described as a “hormone of darkness,” which, for humans with intact light perception who sleep at night and are awake during the daytime hours, does coincide with the notion of a putative role in sleep induction and maintenance. However, elegant chronobiological research in blind humans and across other mammalian and sub-mammalian species has revealed a far more complicated role of this hormone, which in humans is released by the pineal gland following light cues which are transmitted through the retinohypothalamic tract via the superior cervical ganglion. This line of research has shown that the rise in endogenous nocturnal occurs with exposure to darkness independently from sleep per se. Moreover, the magnitude and timing of its release can be also differentially suppressed or, in some cases, enhanced by light presented at particular periods during the 24-hour day. In fact, it is a better marker of circadian phase position of the underlying biological clock within humans than is sleep per se. Yet other clinically driven studies have demonstrated that, when administered exogenously at certain points of the 24-hour day (not always at bedtime), melatonin may be a potent synchronizer of the biological clock. But there is far less agreement and indeed a good deal of controversy as to whether administration of melatonin, at any dose at any time, induces or maintains sleep.

With all this as background, these considerations raise a fascinating question for this RCT: if melatonin successfully decreased nocturia episodes in the MS patients, would it have worked because (a) it helped the patient sleep better OR (b) would it have decreased nocturia episodes by functioning as a chronobiotic, i.e., re-establishing stronger biological rhythmicity, which would directly impact the excess overnight production of urine that constitutes nocturnal polyuria? Moreover, if option (a) represented the neurobiologic substrate underlying an improvement in nocturia, it is entirely possible, given basic science literature on sleep loss per se increasing urine production at night and improved sleep at night decreasing urine output, that improved sleep might itself impact production of urine, even if the melatonin at the dose and formulation used here had minimal impact on circadian rhythmicity. This well-designed and well-thought out study, to be carried out by a top-notch team at one of the world’s leading urological centres (Bristol, UK), will likely be unable to answer this mechanistic question definitively, because unless other independent measures of sleep (e.g., polysomnography) and independent, objective  measures of circadian rhythmicity (e.g., 24-hour body temperature monitoring) were included, the mechanism(s) of action of melatonin on the CNS, even if successful in this MS population, will remain open. In all fairness to the investigators, however, they are not conducting an efficacy trial to elucidate mechanism, which would, it could be contended, only be relevant if clinical benefit was obtained in the first place.

Abstract

BACKGROUND:

Nocturia (the symptom of needing to wake up to pass urine) is common in progressive Multiple Sclerosis (MS) patients. Moderate-to-severe nocturia affects quality of life, can exacerbate fatigue and may affect capacity to carry out daily activities. Melatonin is a natural hormone regulating circadian cycles, released by the pineal gland at night-time, and secretion is impaired in MS. Melatonin levels can be supplemented by administration in tablet form at bedtime. The aim of this study is to evaluate the effect of melatonin on mean number of nocturia episodes per night in MS patients. Secondary outcome measures will assess impact upon quality of life, urinated volumes, lower urinary tract symptoms (LUTS), cognition, sleep quality and sleep disturbance of partners.

METHODS:

A randomized, double blind, placebo controlled, crossover trial consisting of two, six week treatment phases (active drug melatonin 2 mg or placebo), with a 1 month wash-out period in between. The primary outcome (change in nocturia episodes per night) in this two arm, two treatment, two period crossover design, will be objectively measured using frequency volume charts (FVC) at baseline and following both treatment phases. Questionnaires will be used to assess quality of life, sleep quality, safety and urinary tract symptoms. Qualitative interviews of participants and partners will explore issues including quality of life, mechanisms of sleep disturbance and impact of nocturia on partners.

DISCUSSION:

This study will evaluate whether melatonin reduces the frequency of nocturia episodes in MS patients, and therefore whether 'Circadin' has the potential to reduce LUTS and fatigue, and improve cognition and overall quality of life.

TRIAL REGISTRATION:

(EudraCT reference) 2012-00418321 registered: 25/01/13. ISRCTN Registry: ISRCTN38687869.

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