Original Authors: Paul Perry, Ph.D, BCPP, Sam Kuperman,
M.D.
Latest Revisers: Vicki Ellingrod, Pharm.D., BCPP
Creation Date: 1996
Peer Review Status: Internally Peer Reviewed
NOCTURNAL ENURESIS
Nocturnal enuresis (NE) is unintentional urination beyond the usual age of toilet training, usually 6 years for boys and 5 years for girls. It is estimated that between 5 and 7 million children in the US have nocturnal enuresis ("bed wetting"). The majority of enuretics are boys with a prevalence that is higher in poorly educated, lower socioeconomic groups and institutionalized children. However, there is also strong evidence to suggest a genetic component to enuresis. If both parents were enuretic the incidence in the offspring is 77%; if only one parent 44%; and neither parent is enuretic 15%. Among monozygotic twins the concordance rate is 68% while among dizygotic twins the rate is 36%. About 10% of 6-year-olds suffer from nocturnal enuresis according to studies in the US, UK, Israel and African countries (Miller et al 1992). There is a spontaneous remission rate of 15% per year thereafter. Nocturnal enuresis does not have an identifiable organic etiology in 97-99% of the cases. Still it is imperative that the history and physical rule out the organic causes of nocturnal enuresis such as diabetes mellitus, diabetes insipidus, sleep apnea, urinary tract infection, neurogenic bladder, etc. Among the most commonly accepted etiological factors associated with nocturnal enuresis are: smaller than normal bladder capacity; bladder-sphincter dysfunction; nocturnal pylori due to a relative vasopressin (ADH) deficiency; and impaired arousal from deep or delta sleep. Many treatments, both pharmacologic and non-pharmacologic, have been tried with varying levels of success in increasing dry nights and maintaining nocturnal control. Finally, it is estimated that only 38% of parents seek medical help for their child.
Studies have shown that NE and Attention Deficit Hyperactivity Disorder (ADHD) have a rate of co-occurrence of about 30% which is higher than that expected by chance. Beiderman et al (1995) looked at 140 males with ADHD and 120 non-ADHD controls to understand the link between NE and ADHD. Their findings suggested that enuresis does not seem to increase the risk of psychopathology in children after accounting for the presence of absence of ADHD and that enuresis by itself was associated with an increased risk for learning disability, impaired intellectual functioning and impaired school achievement in normal control children but not in children with ADHD. The authors also suggested that among selected children a thorough diagnostic assessment of ADHD be performed in the presence of enuresis.
The most widely utilized classes of medication currently prescribed for nocturnal enuresis are the TCAs, anticholinergic drugs and the synthetic analog of vasopressin, desmopressin.
Tricyclic Antidepressants
Four potential mechanisms have been proposed to explain the TCAs effectiveness in the treatment of NE. These include an antidepressant effect; an antispasmodic and/or anticholinergic effect; alterations in arousal and sleep; and adrenergic neurotransmitter reuptake blockade (Miller et al 1992).
Tricyclic antidepressants, especially imipramine, have been used extensively to treat NE. Kales et al (1977) followed 4 children (3 males, 1 female, 6-14 years) with NE for 68 consecutive nights in a cross-over, placebo controlled study of imipramine. Imipramine 50-100 mg at bedtime for 26 days produced a 65% rate of drug nights whereas a 31 day placebo period only yielded a 21% dry night rate. Dry nights decreased to baseline in all children after withdrawal of imipramine treatment. The decrease in NE frequency was not related to the effects of imipramine on the sleep stages. There was decrease in enuresis in the first two-thirds of the sleep cycle but an increase in events in the later third of the cycle. The later third of the sleep cycle was also associated with an increase in wakefulness. The authors hypothesized that early in the night when sleep is deepest, imipramine decreases bladder excitability and/or increase the child's bladder capacity. This allows the child to continue to sleep without micturation and later in the night when sleep is lighter to be more aware of the stimuli from the bladder.
The small population size of the Kales study (1977) limits the statistical power of this study, but the findings have been replicated by other investigators. Jorgensen et al (1980) conducted a multicenter, double blind, placebo controlled trial of 22 enuretic children utilizing a much more conservative dose of imipramine. Doses of 20-40 mg (1.6 mg/kg/day) for 3 weeks resulted in a significant increase in dry nights that was directly related to the serum concentrations of imipramine + desipramine. They saw no significant increase in dry nights after one week and a tendency towards deterioration after two weeks. A linear relationship between reduction in NE frequency and total imipramine concentration was noted with the threshold concentration for response being 60 ng/ml.
The mechanism of action of the TCAs in enuresis is unknown and is probably not related to antidepressant action because effective serum levels are much lower than needed for adult antidepressant activity (Jorgensen 1980).
Anticholinergics
Anticholinergic drugs have also been used to reduce uninhibited bladder contraction. Uncontrolled studies report that drugs such as oxybutynin and propantheline are beneficial in the treatment of NE. However, there is only one controlled trial that attempted to establish their efficacy in the treatment of NE. Using a crossover design Lovering et al (1988) administered oxybutynin 10 mg at bedtime or placebo for 28 days each in 30 children (25 males, 5 females, 6-14 years) with NE. The blinded study failed to demonstrate a significant difference between the anticholinergic agent and placebo.
NSAIDs
Prostaglandins may play a part in bladder musculature control in enuresis. Al-Waili (1989) hypothesized that since prostaglandin E and F increase detrusor muscle tone and F2a has a potent contractile effect on bladder muscle the use of NSAIDS in the treatment of NE was logical. Indomethacin suppositories 50 mg were administered to 19 children (7 males, 12 females, 6-15 years old) with NE. Using a placebo controlled, double-blind, randomized, crossover design the investigator demonstrated a significant increase in dry nights during the 30 day treatment period. Dry nights per 30 days increased significantly from 4 nights on placebo to 20 nights on indomethacin.
Desmopressin
A new and promising treatment has been found with the synthetic vasopressin analog, desmopressin (DDAVP), which has potent antidiuretic properties with few side effects. Miller et al (1990) completed two multicenter, placebo-controlled trials of desmopressin in a total of 176 severely enuretic children. Doses of intranasal 40 mcg, 20 mcg, and placebo were compared for four weeks. Reductions of wet nights with 40 mcg in trials 1 and 2 were 41% and 34% respectively. With the 20 mcg dose, reductions were 29% and 21%, and with placebo, reductions were 13% and 15%. No serious adverse effects were seen during the trials. Bedwetting behaviors resumed after discontinuation.
Recently the FDA approved desmopressin tablets for the treatment of central diabetes insipidius. Matthiesen et al (1994) conducted a dose-titration, open label 6 weeks efficacy trial of desmopressin tablets for the management of NE. A total of 33 children were included in the study. Of these children, 22 completed 6 weeks of the study and 7 (21%) were considered non-responders. The average number of dry nights in the responding group increased from a mean of 2 ± 1.6 to 5.2 ± 1.9 (p< 0.001) with the 200 mcg and 400 mcg doses of desmopressin tablets decreasing the number of expected enuretic episodes by 63%. Of the 7 children that did not respond to oral therapy, 2 were able to show treatment response with switched to 40 mcg of intranasal DDAVP.
Wetting Alarm Systems
Wetting Alarm systems are a non-pharmacologic treatment alternative for NE. Monda and Husmann (1995) compared the use of the wetting alarm system with observation, imipramine (1.5 mg/kg), and desmopressin (40 mcg intranasal). Patients were given a choice of which treatment option they preferred and after 6 months of treatment were weaned off and evaluated for continence. All children were evaluated at 3, 6, 9, and 12 months after the start of the study protocol. Of the 50 children that were in the observation group, 6% were at 6 months and 16% at 12 months. In the imipramine group (n = 44), 36% were continent at 6 months and 16% at 12 months. Of 88 children treated with DDAVP, 68% were dry at 6 months and 10% at 12 months and in the wetting alarm group (n = 79) 63% maintained continence at 6 months and 56% at 12 months. The wetting alarm system was the only treatment modality that demonstrated persistent effectiveness (p< 0.001), although all forms of therapy improved continence over observation alone (p< 0.001).
Tables 1 and 2 summarize the drug trials and recommended dosages respectively for the treatment of NE. If pharmacologic management is decided upon, three main options are available--imipramine, anticholinergics, or desmopressin. If the child is under 7-years-old, imipramine should not be used due to the risk of toxicity. Anticholinergics such as oxybutynin may be tried, but little clinical evidence is available to support its use. Desmopressin may be the best alternative, however, it is also the most expensive choice at approximately $2.40/10 mcg inhalation. Desmopressin tablets are also an expensive choice with an average wholesale price (AWP) of $1.48 for the 0.1 mg tablets and $2.97 for the 0.2 mg tablet. In children older than 7 years, the choice of drug treatment should be made by taking cost, other medical conditions, and clinical experience into consideration. When determining costs, add the expense of TCA serum concentration tests to the cost of imipramine since drug levels affect therapeutic outcome.
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Table 1. Controlled studies of TCA in nocturnal enuresis. |
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|
Study |
Dose |
Population |
Results |
|
Kales et al 1977 |
IMP 50-100 mg/HS vs placebo |
NE |
Dry nights: |
|
Jorgensen et al 1980 |
IMP 1.6 mg/kg/d vs PLB x 3 weeks |
22 NE |
not equal in dry nights : total IMP |
|
Table 2. Nocturnal enuresis pharmacotherapy. |
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|---|---|---|
|
Drug |
Dose |
Duration |
|
imipramine |
6-9 yo: 25-50 mg/d 10-18 yo: 50-75 mg/d |
3-6 months, then taper |
|
desmopressin |
5-40 mcg/d intranasally |
Adjust dosage on biweekly basis, then taper |
|
oxybutynin |
6-9 yo: 5 mg bid |
2 months, then taper |
ENCOPRESIS
Encopresis is a condition in which children over the age of 4 repeatedly deposit feces involuntarily. The incidence of encopresis is estimated to be 1.5-3% of children, occurring more often in males (Sprague-McRae et al., 1993). Many factors can contribute to encopresis. Many children may deliberately withhold stool, while many children may inherit a biological predisposition to chronic constipation. Regardless of the cause, the retained feces results in large masses of stool that can dilate the colon, causing megacolon. Poor muscle tone then causes fecal incontinence or soiling leading to feelings of low self-esteem (Dawson et al., 1990). The goal of treatment is to empty the colon so that it can return to normal size and function (Sprague-McRae et al., 1993). Standard management has included the use of fiber, enemas, laxatives, lubricants, and behavioral modification. However, other pharmacological agents have been evaluated. The therapeutic endpoint is the termination of soiling and the establishment of regular bowel habits (Murray et al., 1990). A summary of the controlled and uncontrolled trials evaluating the different modes of therapy for encopresis are presented in Table 3.
Ingebo et al. (1988) evaluated 8 encopretic children that had severe fecal retention refractory to outpatient management of high-dose mineral oil. A balanced electrolyte solution of polyethylene glycol (GoLytely) was administered to cleanse the bowel. Weight, CBC, serum electrolyte, urea nitrogen, and creatinine levels were measured before administration and 2 hours afterward. The solution was administered at a rate of 40 ml/kg/hr via nasogastric tube for an average of 22.5 hours. Complete clean-out was achieved in all 8 patients, all lab values were in the normal range before and after administration, and side effects were minimal. This study indicated the safety and efficacy of polyethylene glycol in the intestinal clean-out of encopretic children unresponsive to outpatient management.
Dawson et al. (1990) evaluated 16 encopretic children, 15 boys and 1 girl, with an average age of 11 years, at a state psychiatric hospital. The purpose was to evaluate the effectiveness of medical treatment and behavior modification in treating encopresis. The treatment included phosphate enemas for catharsis, bran cereal and a high-fiber diet to keep the feces soft, and 20-40 ml of mineral oil twice daily orally. Parents were responsible for recording the frequency of bowel movements and soiling, the degree of compliance, and implementing behavior modifications. A relapse occurred in 6 of the patients after the colon clean-out. Therefore, an oral laxative, bisacodyl, was used for a few days omitting the mineral oil. Duration of treatment averaged 5.0 months in the hospital and 2.7b months after discharge. During the first 10 weeks of treatment, the average frequency of encopretic episodes decreased from 4.7 to 1.3 per week. One year after treatment, 14 of the 15 children improved to less than 1 episode per month. This study indicated that joint medical treatment and behavior modification resulted in a decrease in the frequency of encopretic episodes.
Murray et al. (1990) evaluated the use of propulsid (Cisapride) in 12 encopretic children, 8 boys and 4 girls, refractory to treatment with lubricants, enemas, or laxatives. Ages ranged from 2 to 13 years. Propulsid, an agent that enhances bowel motility, is used for gastroparesis, GERD, and chronic intestinal pseudo-obstruction. Propulsid therapy was begun at a dose of 0.2 mg/kg/dose 4 times daily. If no response occurred after 6b weeks, the dose was raised to 0.3 mg/kg/dose 4 times daily. Stool and soiling frequency were assessed biweekly for an average of 61 weeks. Softer stool consistency was reported in 5 patients, while encopresis ceased in 8 patients. These 8 patients then stopped using anticonstipation therapies, too. Only minor side effects were reported. This study showed that propulsid improved stool consistency, soiling frequency, and reliance on anticonstipation therapies in a majority of the children evaluated. Although further investigation is needed, this study suggests that propulsid may have a role in the treatment of encopresis.
Nolan et al. (1991) evaluated 169 encopretic children between the ages of 4 and 16 years. The children were randomly allocated to receive multimodal (MM) therapy (laxative plus behavior modification; n = 83) or behavior modification alone (BM; n = 86). Both groups received a standard behavior modification intervention. In addition, the protocol for the MM group consisted of 3-day cycles of 5 ml 'Microlax' enemas (active ingredient is sodium citrate) on day 1, 5 mg bisacodyl suppository twice daily on day 2 and one 5 mg bisacodyl tablet twice daily on day 3. The maintenance phase consisted of 'Agarol' (active ingredients: liquid paraffin, phenolphthalein, benzoic acid, and sorbic acid) 5-30 ml once or twice daily, senna granules, or bisacodyl tablets. Clinic follow-up was done at 2, 6, 124, 30, and 52 weeks. Compliance with medication in the MM group was excellent in 65%, good in 20%; only 8% were poorly compliant. By 6 months, the MM remission rate was 49%, and there was substantial improvement in a further 11%. The BM remission rate was significantly lower, and the soiling frequency was higher. by 52 weeks, the MM remission rate was 51%, and the BM remission rate was 36%. No patients reported severe side effects. These results showed that fecal continence improved by the addition of laxative therapy to behavior modifications.
McClung et al. (1993) evaluated 16 encopretic children aged 4-12 years using a multiple-intervention program consisting of a complete bowel clean-out and moderate use of laxatives, lubricants, and dietary fiber. Depending on patient preference, isotonic saline enemas, bisacodyl suppositories, and/or phenolphthalein laxatives were used for the intensive bowel clean-out phase lasting 1 to 3 weeks, as needed. The maintenance phase consisted of low-dose mineral oil (0.5 ml/kg/day) and a high-fiber diet. Blood chemistry values, dietary fiber intake, and defecation patterns were evaluated before and after the 6-month study. Fecal soiling episodes averaged 4/week at the beginning of the study to 0.4/week by the end of the 6 months. Blood chemistry values, caloric intake, fat-soluble vitamin status, and nutritional status were not altered. The study confirmed the use of a combined program of multiple-interventions for encopretic children.
Encopresis is a condition with potentially serious implications for the child and family. The results of the controlled study by Nolan et al. (1991) clearly showed that the addition of laxative therapy to behavior modifications was very successful in the resumption of fecal incontinence. Also, this randomized study evaluated a substantial sample size (n = 169) over a significant period of time (n = 52 weeks). The treatment of encopresis can be very complex and lengthy, both pharmacologically and psychologically. Therefore, the combination of laxative therapy plus behavior modification is the best overall approach to treating encopresis.
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Table 3. Efficacy Studies in the Treatment of Encopresis |
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|
Study |
Criteria, Subjects |
Design |
Treatment |
Results |
|
|
Ingebo 1988 |
encopresis, 8 |
open trial |
1. |
polyethylene glycol (GoLytely) |
complete bowel clean-out |
|
Dawson 1990 |
encopresis, 16 |
open trial |
1 |
phos. enema |
decreased encopretic episodes |
|
Murray 1990 |
encopresis, 12 |
open trial |
1. |
propulsid (Cisapride) |
decreased encopretic episodes |
|
Nolan 1991 |
encopresis, 169 |
random allocation |
1. |
MM therapy |
MM therapy improved encopretic episodes |
|
McClung 1993 |
encopresis, 16 |
open trial |
1. |
saline enema, bisacodyl suppositories, phenolphthalein mineral oil, fiber |
decreased encopretic episodes |
REFERENCES
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Biederman J, Santangelo SL, Faraone SV, et al (1995). Clinical correlates of enuresis in ADHD and non-ADHD children. J Child Psychol Psychiat 36:865-877.
Dawson PM, Griffith K, Boeke KM. Combined medical and psychological treatment of hospitalized children with encopresis. Child Psychiatry Hum. Dev. 20:181-90 (1990).
Ingebo KB, Heyman MB. Polyethylene glycol electrolyte solution for intestinal clearance in children with refractory encopresis. Am J. Dis. Child. 142:340-2 (1988).
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Kales A, Kales JD, Jacobson A, et al (1977). Effects of imipramine on enuretic frequency and sleep stages. Pediatrics 60:431-436.
Lovering JS, Tallett SE, McKendry JBJ (1988). Oxybutynin efficacy in the treatment of primary enuresis. Pediatrics 82:104-106.
Matthiesen TB, Rittig S, Djurhuus JC et al (1994). A dose titration, and an open 6-week efficacy and safety study of desmopressin tablet in the management of nocturnal enuresis. J of Urology 151:460-463.
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Murray RD, Li BU, McClung HJ, et al. Cisapride for intractable constipation in children: observations from an open trial. J. Pediatr. Gastroenterol. Nutr. 11:503-8 (1990).
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Sprague-McRae JM, Lamb W, Homer D. Encopresis: a study of treatment alternatives and historical and behavioral characteristics. Nurse Pract. 18:52-3, 56-63 (1993).