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European Urology - Effect of Carbamazepine on Urinary Volume and Osmolality, Water Clearance, and Serum Osmolality in Patients with Primary Enuresis

Saturday, 23 September 2006

Volume 50, Issue 4, Pages 844-850 (October 2006)

1. Introduction

Prostaglandin (PG) and nitric oxide (NO) have various effects on the renal, vesical, urethral, and sympathetic nervous systems; they inhibit Na⁺ tubular reabsorption, inhibit antidiuretic hormone (ADH) secretion, decrease aldosterone secretion, and cause glomerular vasodilatation, natriuresis, and diuresis [1], [2], [3].
PGs were proposed to be important in the pathogenesis of primary enuresis and accordingly strong inhibitors of PG synthesis, for example, indomethacin and diclofenac, were used to treat primary enuresis [4], [5]. Recent studies confirmed this hypothesis, showing that the mean serum and urine PGE₂ concentrations in enuretic patients were higher than in control serum and urine [6]. In addition, others reported that diclofenac sodium and indomethacin were effective in treating nocturnal enuresis, and PG inhibitors have been used to treat urinary incontinence and bladder instability [6], [7], [8]. These studies also substantiate the previous suggestion of the beneficial use of nonsteroidal anti-inflammatory drugs to treat enuresis [4], [5].

Overproduction of NO, mainly at the renal, bladder neck, and urethral levels, might increase urine production and solute excretion and decrease urethral pressure. The last might allow the passage of little urine in the urethra and initiate a bladder contraction, which is exaggerated by the high PG production encountered in enuresis. Therefore, one hypothesis is that both PG and NO are involved in the pathogenesis of enuresis [9].

Carbamazepine (CBZ) is an iminostilbene derivative that is related chemically to the tricyclic antidepressants and is structurally similar to phenytoin. A dose of 400–1000mg/d can be used in children aged 5–15 yr [10]. CBZ is a central nervous system depressant with anticholinergic effect. The drug is used safely for the treatment of simple or complex partial seizures and secondary generalized seizures in infant, adults, and children [11], [12], [13]. It is also used in the treatment of trigeminal neuralgia, in acute mania or prophylaxis of manic depressive disorders, in postherpetic neuralgia, or in phantom limb pain [14], [15]. The major mechanisms of antiepileptic action of CBZ were considered to be its inhibitory effects on Na⁺ channel activity [16], [17]. CBZ reduces Ca²⁺ influx [18]. Plasma concentration of CBZ associated with its antiepileptic action enhanced the synthesis and basal release of monoamine and acetylcholine and inhibited the depolarization-induced glutamate release, whereas more than plasma concentration of CBZ associated with its antiepileptic action reduced them [19], [20]. It has been suggested that CBZ exerts its antiepileptic action by combined effects on the Na⁺ channel blockade together with an enhancement of N-type Ca²⁺ channel activity at resting stage and the blockade of Na⁺channel and P-type Ca²⁺ channel activities at the neuronal depolarizing stage [21].

CBZ inhibits NO and PGE₂ production up to 77% and 88%, respectively. Furthermore, a prominent (94%) decline in the secretory isoform of phospholipase A₂ activity was found in response to CBZ and could contribute to the inhibition of PGE₂ production [22]. CBZ down-regulates cytosolic phospholipase A₂-mediated release of arachidonic acid and its subsequent conversion to PGE₂ by cyclooxygenase (COX) [23]. CBZ abrogates the marked elevation in PGF_2α-forming capacity, a sensitive indicator of luteinizing hormone surge [24]. CBZ dose dependently reduces the inflammatory exudates, the PGE₂-like activity in the exudates, and the substance P concentrations in the exudates [25]. The drug attenuates release of NO in addition to the blockade of voltage-sensitive Na⁺(and Ca²⁺) channels [26]. CBZ was also used to treat nocturnal enuresis, and those not responding to CBZ responded well to stronger PG inhibitors [27].

The aims of the present study were to evaluate the mode of action of CBZ on enuretic patients by assessing its effects on urine output, osmotic clearance, urinary and serum osmolality, creatinine clearance, free water clearance, and fractional sodium excretion, measured before and during carbamazepine treatment, and to determine its efficacy and safety in the management of enuresis.

2. Patients and methods

The study included six boys and two girls with primary nocturnal enuresis (mean age, 10 yr; range, 8–14 yr; Table 1); the criteria for inclusion were age >8 yr, bed-wetting each night, no symptoms of any other diseases, and completely continent during the day. No child had neurologic or urinary tract abnormalities and no treatment was given for 1 mo before the trial. A complete clinical examination and laboratory investigations showed that no child had evidence of bacteriuria, proteinuria, or glucosuria, and all had normal complete blood and renal function tests. None of the children had abnormalities on ultrasonography of the kidney and bladder. The Human Ethical Committee, Dubai Specialized Medical Center, Dubai, approved the study. The study was discussed thoroughly with the children and their parents and they gave their written consent to participate in the investigation after being informed of the purpose and steps of the trial.

Table 1. Patient data


Patient no.	Sex	Age, yr	Weight, kg
1	Female	8	20
2	Female	9	24
3	Male	14	30
4	Male	10	25
5	Male	9	23
6	Male	11	26
7	Male	10	20
8	Male	9	22

The enuretic children were treated for 2 wk with 200mg CBZ each night (20.00hours). The dose is similar to the dose used in earlier work that showed therapeutic effects on frequency of bed-wetting [27]. The overnight urine was collected from 20.00 to 08.00hours; the patient was awaked each 3 hr at night for voiding to avoid bed-wetting. If any patient wet the bed the urine collection was repeated. All the patients completed the investigations, including the nocturnal and diurnal measurement of urine volume, total 24-h urine volume, urine osmolality, serum osmolality, creatinine clearance test, total nighttime urine osmolality, and total daytime urine osmolality. Creatinine clearance was calculated from a standard formula based on height, weight, and serum creatinine and 24-h urinary creatinine levels. Plasma and urinary sodium and potassium were assayed by flame photometry, and other tests by routine methods. Plasma and urinary osmolality was measured by freezing-point depression. The osmotic clearance was calculated as (urine volume×urine osmolality)/plasma osmolality, and clearance of free water as (osmotic clearance – urine volume). The fractional excretion of sodium was estimated as the clearance of sodium×creatinine clearance×100. The maximum functional bladder capacity (FBC) was defined as the largest voided volume during the 24h of the investigation and taken as a percentage of the predicted FBC for age [(age+2)×30)]. Each participant collected the 24-h urine sample. A fasting blood sample was withdrawn at 08.00hours to assay glucose, blood urea nitrogen (BUN), creatinine, and electrolytes. The procedure of urine collection and blood sampling was repeated after 15 d of CBZ treatment. On the day of investigation, physical activity, meals, and fluid intake before and after CBZ treatment were similar for each patient. The patients abstained from tea, coffee, and cola-based drinks during the day of investigation. During CBZ treatment, the patients were observed for any side-effects, such as headache, dizziness, allergy, gastric pain, abnormal motion, gastrointestinal symptoms, and skin rash.

All the values were expressed as the mean (±SD) and the Student t test was used for the statistical analysis, with p<0.05 taken to indicate significant differences.

3. Results

There was a marked decrease in the frequency of nocturnal bed-wetting episodes; dry nights were increased from zero before treatment to 9.7 (2.8) dry nights for 15 d of treatment (65%) (Table 2). CBZ decreased the 24-h urinary frequency from 8.3 (1.7) to 6 (0.8; p<0.05). No side-effects were reported with CBZ. The maximum FBC decreased from 240 (6.2) to 154 (17) ml after CBZ treatment.

Table 2. Measurements before and during carbamazepine treatment


Variables	Before	After	Percent
Night urine volume, ml	426±90	235±50*	45
Day urine volume, ml	410±113	255±161*	38
Total 24-h urine volume, ml	835±121	492±228*	41
Frequency of mictrurition/24h	8.3±1.7	6±0.8*	28
Functional bladder capacity (night), ml	232±9	147±17*	37
Functional bladder capacity (day), ml	118±13	102±54	14
Functional bladder capacity (total), ml	240±6	154±17*	36
Total urinary sodium (mmol/24h)	82±45	79±51	3
Day urinary sodium concentration, mmol/l	95	151	59
Night urinary sodium concentration, mmol/l	80	189	138
Fractional excretion of sodium, %	0.45	0.95	111
Serum sodium concentration, mmol/l	142.8±1.8	140.2±2
Serum osmolality, mOsm/l	284±3.4	277±2.9*	2
Urine osmolality night, mOsm/l	469±82	673±66*	43
Urine osmolality day, mOsm/l	729±64	794±99	9
Urine osmolality 24h, mOsm/l	487±147	660±33	36
Creatinine clearance, ml/min	105±20	86±19*	19
Osmotic clearance, ml/min/kg	1.48±0.33	0.93±0.38	37
Free water clearance, ml/min/kg	0.9±0.25	0.59±0.23*	34

* p<0.05.

CBZ reduced the total 24-h, night, and day urinary volumes; the day urine volume decreased by 38%, the reduction was greater at night (45%) as was total 24-h volume (41%; Table 1). The day-to-night urinary volume ratio increased from 0.96 to 1.08. CPZ decreased the clearance of free water by 34% and increased the 24-h urine osmolality by 36%, night urine osmolality by 43%, and daytime urine osmolality by 9%. CBZ decreased serum osmolality (p<0.05). CBZ also decreased osmotic clearance by 37%.

The absolute amount of sodium excreted was decreased. There were insignificant changes in serum sodium concentration with CBZ treatment; the fractional excretion of sodium was increased by CBZ. CBZ decreased the creatinine clearance from 105.2 (20.4) to 85.5 (18.8) ml/min (19%; p<0.05).

4. Discussion

The American Psychiatric Association has defined bed-wetters as children older than age 5 yr who have urinary incontinence at night. Delayed functional maturation of the central nervous system, which reduces the child's ability to inhibit bladder emptying, is one of the factors that can cause primary enuresis. Genetic factors may also play a role in enuresis. Further, patients with nocturnal enuresis have difficulties in waking [28]. Children with enuresis did not show a normal rise in the nocturnal secretion of ADH [29]. It has been suggested that a somatic disorder and nocturnal polyuria are encountered in bed-wetting children [30]. The nocturnal polyuria was due to absence of the normally occurring increase of ADH in plasma during the night [31]. Nocturnal bladder overactivity is a significant cause in at least one third of enuretic children [32]. Nocturnal polyuria is an important pathogenetic factor in around two thirds of enuretic children. Bed-wetters without nocturnal polyuria, those who do not respond well to desmopressin, should be suspected to have a reduced bladder capacity [33]. Bladder capacity might affect renal function and glomerular filtration; a distended bladder with a large volume of urine might reduce the glomerular filtration rate and urine production, whereas an empty bladder or little urine in the bladder might abolish this effect or even facilitate increase in glomerular filtration rate or urine production from kidney. If this could be confirmed, a small bladder capacity or a small amount of urine in the bladder might trigger high urine output at night (nocturia) and then enuresis (N.S.A-W., personal communication). Nonpharmacologic treatments of nocturnal enuresis include motivational therapy, behavioural conditioning, and bladder-training exercises. Pharmacologic therapy includes imipramine, anticholinergic medication, and desmopressin; these drugs have been used with varying degrees of success.

A major interaction has been suggested between NO and PG in mediating the renal response to various situations. In addition to PG, NO production in the urinary system may be involved in the pathophysiology of enuresis. Serum and urine PG levels were significantly higher in enuretics than in controls [6]. These findings confirm the earlier hypothesis that PGs are important in enuresis [4], [5], [27].

CBZ inhibits NO production [22]; like indomethacin, CBZ could inhibit both COX and nitrous oxide synthase (NOS), and hence might improve enuresis by inhibiting PG and NO production in the urinary system. The present results show that CBZ markedly decreased the 24-h urine, nighttime and daytime volumes. CBZ also decreases the clearance of free water and increases the day-to-night urine volume ratio. These reductions in volume are accompanied by increased urine osmolality and decreased osmotic clearance. A urinary concentration of sodium was markedly increased but the absolute amount decreased in the urine of enuretic children taking CBZ. CBZ decreases creatinine clearance by 19%; in another study, indomethacin, which has similar effects on enuretics, decreased creatinine clearance by 20% in enuretic children [9].

The FBC was decreased after using CBZ, despite a significant reduction in the voiding frequency. The significant effect on FBC might be a result of the significant reduction in urine volume. Reduced FBC might not be the only cause of primary enuresis because a reduction in liquid intake in the evening or using diuretics is not always effective for enuresis. Obviously, the main action of CBZ in the present patients was to reduce urinary output.

The high concentrations of solutes as a result of the marked reduction in water excretion increased the osmolality, mainly at night. This might be a result of inhibition of both PG and NO, which increased diuresis. Urinary osmolality was increased by CBZ, less so than the increments caused by indomethacin [9]. CBZ decreases night and day urine volume greater than does indomethacin. The antidiuresis ascribed to CBZ is mediated by a decrease in free water clearance, which may be mediated by increases in ADH. CBZ increases renal sensitivity to normal plasma concentration of ADH and resetting of osmoreceptors [34]. It decreases the ability to excrete water load and causes lower free water clearance and high urine-to-plasma osmolality ratio [35]. In response to fluid restriction, enuretics had significantly greater increases in plasma ADH than had comparable controls and thus enuretic children had a higher secretion of ADH and did not have ADH deficiency [36]. There is a defect at the vasopressin receptor level, rather than vasopressin deficiency, that has to be supplemented. The basis for using desmopressin is that a missing circadian rhythm of ADH secretion results in nocturnal hormone deficiency in enuretics. However, patients with primary enuresis have no greater nocturnal urine production than controls; there were no differences between the plasma osmolality and rhythm of ADH secretion. Enuretic children need significantly higher ADH levels to maintain constant plasma osmolality [35]. In addition, CBZ exerts an ADH-like effect [37]. Therefore, CBZ may help patients with increased ADH or its ADH-like activity.

The action of CBZ might be similar to that of desmopressin. CBZ could also stimulate ADH and decrease the absolute amount of urinary sodium excretion. It might suppress bladder contractility and increase urethral tone by inhibiting both NO and PG production. These aspects need further investigation.

Using a combination of CBZ, indomethacin, or desmopressin for primary enuresis might have synergistic effects, giving greater improvements and allowing reduced doses and ultimately side-effects.

It was thought unethical to use placebo and expose children to long series of testing and food restriction. The comparison was made within the group, before treatment and during treatment. A limitation of study was the few number of patients recruited. Thus, other controlled studies are needed to substantiate this possibility.

5. Conclusion

The study confirms our previous finding that CBZ was effective in the treatment of enuresis. CBZ decreases frequency of bed-wetting and micturition, urine volume, free water clearance, osmotic clearance, creatinine clearance, and serum osmolality. CBZ increases the day-to-night urinary volume ratio, the 24-h urinary volume osmolality, and night urine osmolality. These actions may explain the mechanism of action of CBZ. No side effects were reported during the time of trial. CBZ may be used in the treatment of the enuresis alone or in combination with other medications, particularly in patients not responding to other measures. Future studies with larger series should help to define the best period of treatment because CBZ cannot be recommended as chronic treatment for children with enuresis.

Editorial comment

Daniele Porru' ); document.write( addy68256 ); document.write( '<\/a>' ); //-->\n This email address is being protected from spam bots, you need Javascript enabled to view it ">

In their paper Al-Waili et al. investigate the effects of carbamazepine in a small group of patients with primary nocturnal enuresis. The author already studied the molecole in the past [1], with similar results versus treatment with placebo. Carbamazepine is chemically related to imipramine. It can reduce prostaglandin E2-like activity in inflammation, it can cause overflow urinary incontinence, increased bladder capacity, sensitise renal tubules to antidiuretic hormone, leading to antidiuresis. This encouraged to use carbamazepine to treat primary enuresis. However, this drug can expand the effect of other antiepileptics prescribed for seizures, and therefore should be recommended with caution particularly in a population of children and for a long period of time; usually this is not required in case of monosymptomatic nocturnal enuresis, which is bedwetting with normal daytime urination; this, in fact, appears to be a delay of functional maturation of bladder control by the central nervous system; it is probably reflected in the higher rate of bedwetters among developmentally delayed children and those with low birth weights [2].

The final steps of maturation are taken when, around the age of 4 or 5 years, the child has learned to postpone micturition and is able to initiate micturition even when the bladder is not full. In most cases of occasional nocturnal enuresis in childhood, medical treatment is not required, and in any case it should not be recommended for a very long period of time. Moreover, larger studies should be carried out to confirm its effects and particularly its reliability. When drug treatment is not indicated, or side effects are observed with its use, behavioural modification, particularly conditioning therapy (enuretic alarm system), which is the most commonly recommended form of therapy, should be employed, with a cure rate of about 70% [3].

References

38. Al-Waili NS. Carbamazepine to treat primary nocturnal enuresis: double-blind study. Eur J Med Res. 2000;5:40–44.

39. Alon U. Nocturnal enuresis. Pediatr Nephrol. 1995;9:94–103.

40. Cendron M. Primary nocturnal enuresis: current. Am Fam Physician. 1999;59:1205–1214.

Editorial comment
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Involuntary voiding of urine during sleep is the most prevalent problem in childhood. Pathophysiology of nocturnal enuresis (NE) is still not completely understood. Lack of nocturnal vasopressin release with consequent polyuria during sleep, detrusor overactivity during the night with potential reduction of bladder capacity, and lack of arousal from sleep to full bladder sensations are the main mechanisms considered to explain the nocturnal enuresis in children [1].

It has been argued that parental concerns and child distress represented the main motivations to start therapy in patient older than 5 years. Recently, the International Consultation on Incontinence, proposed a pragmatic approach for the management of NE, where the mainstays were problem explanation and providing instruction about daily habits, underlining the importance of having regular fluid intake, regular voidings, and relaxed routine at bedtime.

Enuresis alarm is the most effective means recommended in the treatment of patients with difficulty in waking up during the night (level of evidence 1 – Grade A of recommendation). Arousal and dry bed training can represent additional behavioural tools to improve waking up and toileting ability. Desmopressin is the only recommended drug (level of evidence 1 – Grade A of recommendation) to treat the increased output of nocturnal urine [2]. Nevertheless, nocturnal polyuria in children may also attributed to an increase in nocturnal excretion of sodium related to the effects of prostaglandin (PG) and nitric oxide (NO) at renal level [3]. Carbamazepine (CBZ) is a tricyclic antidepressant, able to inhibit the PG and NO production [4].

In their paper Al-Waili et al. reported about 8 children with severe (bed-wetting each night), mono-symptomatic, primary NE, who were treated by CBZ at dosage of 200mg each night (20.00hours) for 2 weeks. The authors suggested that CBZ reduced 24-h urine nighttime and daytime volumes, increased urine osmolality, and decreased free water clearance, osmotic clearance, and frequency of micturition. During the 2-week of the study, indeed, the Authors reported a decrease of the mean number of dry nights from 15 to 9.7 (less than 40%), which is usually considered as non-response [5]. In addition, the clinical results might be influenced by the concomitant dry bed training (patients were awaked each 3hours at night to void and avoid bed-wetting). The number of patients included in the analysis, study designed (non-controlled), and results reconfirm the statement of the 3rd ICI that CBZ should not be recommended as routine treatment of NE at this stage. I believe that larger, controlled studies are needed to demonstrate clinical efficacy of CBZ in the treatment of mono-symptomatic NE. To date, the best period of treatment should be considered only a secondary, less important outcome.

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Acknowledgement

The authors would like to thank Haj Saeed Lootah, Chairman of Trustees, Islamic Establishment for Education, Dubai, for his kind support. The study was not based on any financial support from drug companies or academic establishments.

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Noori S. Al-Waili^a, Hamza Al-Waili^a, Khelod Y. Saloom^a, Thia Al-Waili^a, Ali Al-Waili^a, Mohammod Akmal^b, Faiza Al-Waili^b

^a Al-Waili's Charitable Foundation for Science and Trading, New York, NY, USA
^b Dubai Specialized Medical Center and Medical Research Laboratories, Islamic Establishment for Education, Dubai, UAE

Accepted 15 February 2006 published online 27 February 2006.

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