US Pharm. 2017;42(5):32-35.

ABSTRACT: Nocturnal enuresis can be frustrating for children and their families as the child ages, but clinical intervention generally is not warranted until the child is 5 to 7 years old. If nocturnal enuresis is left untreated, resolving the problem can become more difficult. A diagnosis of nocturnal enuresis requires careful coordination of both the patient and the family for optimal outcomes and to avoid relapse. Many treatment plans are founded on motivational therapy and enuresis alarms. Desmopressin and imipramine are FDA-approved for the treatment of nocturnal enuresis in patients older than 6 years. Use of these medications requires thorough counseling by a pharmacist to ensure that the family understands that these medications cannot cure nocturnal enuresis, but are used only for symptom treatment.

In the United States, 5 to 7 million children experience isolated bed-wetting at night, clinically known as nocturnal enuresis.¹ This nighttime voiding is not seen as problematic until the child is 5 years old, and even then some professionals will not intervene until the child is 7 years old. Achieving the ability to control bladder function is usually the last step in toilet training.

ETIOLOGY

A child with primary nocturnal enuresis has never achieved a satisfactory period of nighttime dryness; this classification accounts for about 80% of patients. Secondary nocturnal enuresis, the development of enuresis after a dry period of at least 6 months, is typically seen in children who are going through a remarkably stressful experience, such as a shift in family dynamics (e.g., divorce, birth of a sibling), and accounts for 20% of cases.²

Monosymptomatic nocturnal enuresis is defined as enuresis in a child without lower urinary tract symptoms and no history of bladder dysfunction. Nocturnal enuresis may result from one or a combination of several possible factors. The major mechanisms include nocturnal polyuria, detrusor overactivity, and disturbed sleep.³

Nonmonosymptomatic nocturnal enuresis is the term for enuresis in a child who has other lower urinary tract symptoms: increased (≥8 times/day) or decreased (≤3 times/day) voiding frequency; intermittency (micturition occurs in several discrete spurts); straining (application of abdominal pressure to initiate and maintain voiding); hesitancy (difficulty initiating voiding); urgency; weak stream; holding maneuvers (strategies used to postpone voiding); daytime incontinence; feeling of incomplete emptying; postmicturition dribble; and genital or lower urinary tract pain.³

PATHOPHYSIOLOGY

The development of bladder control appears to follow a progressive timeline. A child first becomes aware of bladder filling; develops the ability to suppress detrusor contractions voluntarily; and, finally, learns to coordinate sphincter and detrusor function. The child usually achieves these skills by approximately 4 years of age, at least for daytime control. Nighttime bladder control is achieved much later than daytime regulation and is not expected until age 5 to 7 years.⁴

Regulatory hormones, specifically antidiuretic hormone (ADH), play an essential role in urine output and are secreted at night, following circadian rhythm. A nighttime rise in ADH would signal the body to create less urine. It is postulated that children with nocturnal enuresis have not developed this circadian rhythm, and as a result have nocturnal polyuria.⁴

Bed-wetting may be associated with neuropsychiatric problems like intellectual disabilities, low self-esteem, and attention-deficit/hyperactivity disorder (ADHD). A study by Salehi and colleagues recommends that children also be evaluated for generalized anxiety disorder as a differential diagnosis.⁵

EPIDEMIOLOGY

The prevalence of bed-wetting decreases as children age. At age 5 years, it is seen in 15% to 25% of patients. At age 12 years, 8% of boys exhibit enuresis, compared with 4% of girls.⁴ Bed-wetting is twice as common in boys as in girls. Bed-wetting often resolves on its own, but only in mild cases.⁶ Cases that do not resolve on their own can be very frustrating, especially in older children. It is important to note that the longer enuresis continues, the probability of spontaneous resolution decreases. Enuretic children aged >10 years have significantly more daytime urinary symptoms and incontinence.⁶

DIAGNOSTIC FEATURES

Evaluation includes a history, physical examination, and urinalysis. The history should cover the frequency and trend of nocturnal enuresis; stooling, soiling, and constipation (seen in 33%-75% of patients); prior interventions; medical conditions (especially sleep apnea, diabetes, sickle cell disease/trait, urinary tract infections, gait, or neurologic abnormalities); family and social history; assessment of how the problem affects child and family; and behavioral history (screen for psychiatric comorbidity).^1,4

The voiding diary is a key component of a complete history, and it should contain at least a week’s worth of entries. The diary should include timing of daytime voids (to estimate patterns); daily fluid intake (differential between diabetes, kidney disease, or excessive fluid intake without psychological stimuli, termed psychogenic polydipsia); volume of voided urine (to estimate capacity); and lower urinary tract symptoms (discussed earlier).¹

TREATMENT APPROACH

It is essential for the provider to define expectations for both the parents or caregivers and the child. Often, parents want reassurance that the problem is not caused by a physical abnormality; others are not interested in starting long-term treatment programs. The provider should emphasize that bed-wetting is not the child’s fault and that the child should not be punished for it. Surveys have found that 25% to 33% of parents punished their children for wetting the bed, and in some cases punishment involved physical abuse. If a parent or caregiver states that the child is deliberately wetting the bed, potential abuse should be considered. Parents or caregivers who blame or express anger or negativity toward the child may need additional support in coping, and the intervention of a pediatric specialist may be necessary.³

A carefully constructed treatment plan often involves several modalities used either in sequence or in combination. It should be discussed up front that treatment can be prolonged, failure is typical in the beginning, and the potential for relapse exists. Parents and caregivers must be willing to fully participate, and the overall family environment must be supportive. Therapy is goal-oriented, and consistent follow-up is necessary. Goals of treatment include staying dry on specific occasions (e.g., sleepovers, summer camp), reducing the numbers of wet nights, lessening the impact of enuresis on the child and the family, and avoiding recurrence.⁷

MANAGEMENT

Monosymptomatic nocturnal enuresis can generally be managed by a primary care provider. Children with refractory enuresis may benefit from the inclusion of a specialist in their care plan. This could be a developmental-behavioral pediatrician or a urologist, if structural abnormalities are suspected.³

Management of primary nocturnal enuresis may involve one or a combination of interventions: education and reassurance, motivational therapy, enuresis alarms, and medications.⁷

Adherence is an essential part of a successful therapeutic plan. A study by Baeyens and colleagues concluded that the best predictor of good adherence is a positive perception of one’s physical appearance and, to a lesser extent, low levels of stress related to treatment of the disorder.⁸

Nonpharmacotherapeutic Methods

Education and Reassurance: The International Children’s Continence Society considers education and reassurance the initial step of any treatment plan, including the following guidance^2,7:

• Enuresis is common; 16% of children aged 5 years experience at least one episode per week.

• Enuresis is not the fault of the child or parent/caregiver.

• Reduce the impact of bed-wetting by using bed protection, washable or disposable products, and deodorizers that specifically mask the smell of urine; thoroughly washing the child before dressing; and using emollients, such as diaper rash creams, to prevent chafing.

• Keep a calendar of wet and dry nights to track the effect of interventions.

• Schedule voiding just before bedtime and during the night. If the child wakes at night, he or she should be escorted to the toilet by parent or caregiver.

• High-sugar and caffeine-containing drinks should be avoided, especially at night.

Motivational Therapy: This therapy encompasses positive-reinforcement systems and responsibility training. A reward system, such as a star or point chart, may be implemented wherein the child earns a star or point each night he or she remains dry. After a certain amount of stars or points has been reached, the child receives a prize. Another technique is the use of connect-the-dot pictures: The child connects two dots for every dry night, and once the picture is completed, a prize is awarded. In responsibility training, children are given duties that reflect their maturity level and are presented in a nonpunitive way. A younger child might be asked to strip the bed after a nondry night, and a more mature child might be expected to do the laundry.⁴

Enuresis Alarms: Pharmacists may encounter parents or caregivers who are seeking advice on specific types of alarms or how to order them. These devices have been shown to be the most effective treatment for nocturnal enuresis.⁹ Compared with other skill-based or pharmacologic interventions, alarms have a high success rate (75%) and a lower relapse rate (41%).⁴ These alarms work by negative conditioning. A sound or vibration goes off and awakens the child if he or she voids while asleep; the child then gets out of bed and finishes voiding in the toilet or holds the urine until later. The child learns to wake or to inhibit contraction of the muscles involved in micturition in response to the physiological condition before voiding. In terms of symptom resolution, at least 2 weeks are needed to see any type of response, and it can take up to 15 weeks for bed-wetting to completely cease.⁷ It is important to note that many insurance companies will not cover these devices.

A large treatment hurdle is compliance; dropout rates range from 10% to 30%.⁴ Alarms work best for well-motivated families and children with frequent enuresis—i.e., more than two episodes per week. Potential predictors of poor compliance include an unstable or chaotic family situation; behavior deviance by the child; high level of maternal anxiety; lack of child or parent/caregiver concern about bed-wetting; low parental/caregiver education level; and parent/caregiver history of using alarm devices, with negative connotations.^4,7

Pharmacotherapy

Medication is not recommended as first-line treatment and should not be used in children younger than 6 years. It must be stressed that medication will not cure nocturnal enuresis; it will only treat the symptoms. Two commonly used drugs are desmopressin and imipramine, both of which are FDA-approved for this indication.

Desmopressin (DDAVP or Minirin): This medication boosts levels of the hormone ADH, forcing the body to make less urine, and the urine that is produced is more concentrated. The recommended dosage is 0.2 mg by mouth at bedtime, and it may be titrated up to 0.6 mg, depending on patient response.¹⁰ It may be used in short-term situations, such as sleepaway camps.¹¹ Fluid intake should be limited to 1 hour before administration, the next morning, or at least 8 hours after administration. Therapy should be interrupted for hot weather and acute illness like systemic infections, fever, recurrent vomiting, or diarrhea. These situations require increased fluid intake and could affect the efficacy of the medications. Overall response to treatment ranges from 60% to 70%, although some studies have shown relapse to be as high as 50% to 90%, especially when the high cost of the medication is considered.¹² The FDA recommends against the use of the nasal sprays in children, based on reports of dramatic changes in electrolytes resulting in seizures or death. The spray gained an indication for nocturia in March 2017, but  solely in adults; the brand name is Noctiva.¹³ The most common adverse effects include headache, abdominal cramps, hyponatremia, anorexia, nausea, taste disturbances, and blurred vision. Monitoring parameters (although not routinely used) include serum sodium and urine osmolality.¹⁰

Imipramine (Tofranil): This second-line medication is typically reserved for when other therapies fail. It is not known exactly how imipramine exerts its action to prevent nocturnal enuresis, but prevention is believed to be linked to the drug’s ability to block acetylcholine receptors. Initial dosing is 25 mg by mouth given 1 hour before bedtime; if no response is seen after a week, the dose may be increased to 75 mg. The maximum daily dosage should not exceed 2.5 mg/kg/day. Doses above 75 mg have not been shown to improve efficacy, and they tend to increase side effects.¹⁴ Once appropriate results have been achieved, a slow taper should be initiated to reduce the likelihood of relapse and withdrawal symptoms. These symptoms may include cholinergic rebound (e.g., insomnia), dizziness, nausea, vomiting, and diarrhea. This taper is recommended because pediatric patients who relapse while on an imipramine trial typically do not respond to a repeat course of the drug. Imipramine has been associated with arrhythmias after toxic ingestion (>500 ng/mL), and many practitioners have begun to eschew it as a precaution.^11,15 The prescribed dosage will not cause these irregularities, but it is important to counsel that only parents should give this medication and that it should be stored out of the reach of children to prevent accidental ingestion. Common adverse effects include anticholinergic effects, anxiety, irritability, insomnia, loss of appetite, and moodiness. Monitoring parameters include therapeutic drug levels (180-250 ng/mL) and ECG, if cardiovascular dysfunction is suspected.¹⁴

Anticholinergics: Oxybutynin (Ditropan) may help reduce bladder contractions and increase bladder capacity by competitively antagonizing the M1, M2, and M3 muscarinic acetylcholine receptors.¹⁶ It is typically used as adjunctive therapy when other pharmacotherapies are unsuccessful. Recommended dosing is 5 to 10 mg by mouth at bedtime.¹⁶ A meta-analysis by Chua and colleagues demonstrated increased efficacy when oxybutynin was combined with desmopressin in desmopressin-resistant patients, and the combination therapy was well tolerated.¹⁷ Oxybutynin can cause anticholinergic effects such as dry mouth, dry eye, blurred vision, and gastrointestinal disturbances in up to 76% of patients.¹⁸ Oxybutynin crosses the blood-brain barrier, and central nervous system (CNS) effects were greater in children compared with adults in a recent study by Gish and colleagues (36% vs. 11%, respectively). Hallucinations were the most commonly reported CNS effect, followed by agitation, sedation, confusion, amnesia, and abnormal dreams.¹⁹

ROLE OF THE PHARMACIST

Pharmacists can play a key role in the management of patients with nocturnal enuresis. They can offer encouragement to both patients and families (see SIDEBAR 1 for patient resources). In counseling sessions, it is critical to stress that adherence is important and that medication is not a cure. Explaining which side effects of prescribed medications are common and which should be reported to the prescriber is also important. Parents and caregivers may be overwhelmed, especially when they are trying to select an enuresis alarm. Many pharmacists can order these alarms from their wholesalers. Sometimes, the parent or caregiver may be directed to online retailers such as bedwettingstore.com or onestopbedwetting.com to compare features and prices. In some cases, parents or caregivers are permitted to physically punish a child for wetting the bed. In many states, pharmacists are mandatory reporters of child abuse, and if abuse is suspected, the pharmacist should call the 24-hour Childhelp National Child Abuse Hotline: 1-800-4-A-CHILD (1-800-422-4453).

CONCLUSION

Bed-wetting is due to inadequate muscle control during the night, and this type of control is one of the last stages of toilet training. Many medical practitioners do not see this as a problem until the child is at least 5, if not 7, years of age. Successful treatment plans require motivated participants and high adherence rates to curtail the problem. Pharmacists can help families deal with the struggles associated with bed-wetting by being a source of encouragement and information during treatment.

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