Current Approaches to Nocturnal Enuresis: Pearls for the Family Doctor

Patients’ Perspective A survey reported that 68% of parents said that their child’s paediatrician or primary care provider had never addressed bedwetting during a routine visit, regardless of the child’s age 1 Most parents believe that NE is not a physical condition and are uncomfortable initiating a dialogue with physicians 1 Adapted from Dunlop et al., Clinical Pediatrics 2005;44:

Inadequate treatment of NE has psychological ramifications including impaired personal, social and emotional behaviour 1,2 –Only parental fighting and divorce are perceived by patients as worse than bedwetting 3 Adapted from Fergusson et al. Pediatrics 1986; 78: Butler et al. BJU intern 2002; Vol 89; issue 3; Van Tijen et al. British Journal of Urology 1998; 81 Suppl 3: Patients’ Perspective

Most parents (80%) believe that children wet the bed because they are stressed or worried, or in some cases simply out of laziness 1 –A survey by the Enuresis Resource Information Centre (ERIC),UK-based charity Adapted from 1 Parents’ Perspective

MDs maintain the notion that patients will outgrow the problem and defer treatment 1 Family Physician residents receive limited training in NE –Not on the curriculum for post graduate students in the 6 Ontario medical schools 2 Health Canada recently issued a safety bulletin that directly impacts a common treatment option for NE 3 Adapted from Gimble et al. Clin Pediatr (Phila). 1998;37(1): Personal communication Physicians’ Perspective

Involuntary discharge of urine at night by children old enough to be expected to have bladder control –Persists beyond the age of 5 years –Total bladder control never achieved or relapsed –Incidence of more than twice weekly –Continent during the day –Types of nocturnal enuresis PNE when bladder control has never been attained SNE previously dry for a at least six months Adapted from Canadian Pediatric Society. Management of primary nocturnal enuresis. Paediatrics & Child Health 2005;10(10): Definition of NE 1

Adapted from Fergusson et al., Pediatrics 1986; 78(5): Robson et al. Curr Opin Urol 2008,18; Klackenberg et al., Acta Paediatr Scand 1981;70:453 3 Yeung et al. BJU Int 2006;97: Nocturnal Enuresis (%) Age (years) NE resolves spontaneously at a rate of 15% a year 2 NE affects twice as many boys than girls 3 Prevalence 1,4

Genetic predisposition 1 –Family history: one parent 44%, two parents 77% Excessive urine production 2 –Due to inadequate amount, or response to ADH at night Deep sleep and arousal disorder 3 –Lack of awareness of a full bladder during sleep Adapted from Von Gontard et al. J Urol 2001; Vol. 166, 2438–43. 1 Rittig et al. Am J Physiol 1989; 256(4 Pt 2):F Wolfish NM. J Urol 2001; 166(6): Etiology

Diminished functional bladder capacity 1 Slow development of bladder control 1 Emotional and behavioural issues are not causative, but may influence treatment outcome 2 Adapted from Wolfish NM. J Urol 2001; 166(6): CPS-management of primary nocturnal enuresis (revised Aug 2007) 2 Etiology

Urine Volume Bladder Contractions Sleep Arousal ENURESIS Adapted from Wolfish et al., J Urol 2001; Vol. 166, 2444–7. Causes of Enuresis: A Triad 1

Mean variation in urinary excretion rate ml/hour P<0.001 Adapted from Rittig et al. Am J Physiol 1989 Apr;256(4 Pt 2):F Circadian Urine Production

Mean variation in plasma antidiuretic hormone (ADH) P avp (pg/ml) P<0.001 Adapted from Rittig et al. Am J Physiol 1989 Apr;256(4 Pt 2):F Circadian ADH Production

Psycho-social impact 1,2 –Low self-esteem –Shame, embarrassment –Guilt Parents become intolerant of the bedwetting 2 Interferes with age appropriate peer activities 1,2 Adapted from Hägglöf et al., Scand J Urol Nephrol 1997;31: Butler et al, BJU intern 2002; Vol 89 issue 3; Impact of Enuresis on Children

Bedwetting is a medical condition It is mostly caused by the lack of naturally occurring messenger that reduces urine production to a non- bedwetter’s volume at night 2 –Leads to an overproduction of urine, often more than a child’s small bladder can hold 1 As the children grow, most will eventually stop wetting the bed Adapted from Butler et al, BJU Intern 2002; Vol 89; issue 3; Djurhuus et al., Scand J Urol Nephrol Suppl 1992;141:7-17; discussion NE: It’s NOT the Child’s Fault 1

Screen for NE as most patients are uncomfortable initiating dialogue 1 Investigate history, conduct physical examination and urinalysis 2 –Urinanalysis not always needed –Investigate family history –Establish if NE is primary or secondary Primary NE: started at birth & is continuous Secondary NE: previously dry for at least six months Adapted from Dunlop et al., Clinical Pediatrics Canadian Pediatric Society. Management of primary nocturnal enuresis. Paediatrics & Child Health 2005;10(10): Diagnosis

Rule out other possible conditions 1 –Structural or neurological problems –Storage or voiding dysfunctions –Daytime wetting –Urinary tract infection –Polyuric conditions Diabetes mellitus, diabetes insipidus, chronic renal failure, renal tubular acidosis, renal dysplasia, Bartters syndrome Adapted from Hjalmas et al. J Urol 2004;171: Diagnosis

Increase the number of dry nights 1 Minimize the emotional impact of NE 1 –Establish a positive environment to help the child become dry –Protect & improve self-esteem as NE is not the child’s fault. Minimize feelings of guilt & shame Note –Therapy is a stepwise process –Partial response better than no response –May require years of continuous therapy Adapted from Canadian Pediatric Society. Management of primary nocturnal enuresis. Paediatrics & Child Health 2005;10(10): Treatment Goals

Child to empty the bladder at bedtime Limit fluid consumption & eliminate caffeine –Late afternoon and onwards Clarify the goal of getting up / using the toilet Take the child out of diapers –Consider pull-ups or training pants Include child in morning cleanup in a non-punitive manner Adapted from Canadian Pediatric Society. Management of primary nocturnal enuresis. Paediatrics & Child Health 2005;10(10): (REVISED AUG 2007) Common Management Strategies 1

Non-pharmacological –Wet alarm –Behavioural therapyX Pharmacological –Desmopressin acetate –Tricyclic antidepressantsX / extreme caution –Anticholinergics, amphetamine, ephedrine, atropine, furosemide, diclofenacX Adapted from Canadian Pediatric Society. Management of primary nocturnal enuresis. Paediatrics & Child Health 2005;10(10): Treatment Approaches 1

Approaches recommended by both the Canadian Paediatric Society 1 and the WHO 2 –Wet alarm –Desmopressin acetate Adapted from Canadian Pediatric Society. Management of primary nocturnal enuresis. Paediatrics & Child Health 2005;10(10): van Gool JD, et al. International Consultation on Incontinence 1998–Monaco; WHO: Treatment Approaches Supported

Appropriate care for the individual patient needs to consider patient preferences –Better treatment outcomes are achieved when parents / patient are involved in making the decision about choice of treatment 1 –Treatment modalities require consistent support and cooperation from the child and the family and are unlikely to succeed in their absence 2 Adapted from Monda et al, J Urol Aug;154:issue 2, Tarun Gera et al.,Nocturnal Enuresis In Children. The Internet Journal of Pediatrics and Neonatology Volume 2 Number 1. 2 Patients Involvement

Adapted from Canadian Paediatric Society Positioning Statement, Tietjen et al. Mayo Clin Proc 1996;71: Wolfish et al. J Urol 2001; Vol. 166, 2444–7. 3 Butler RJ et al. Scand J Urol Nephrol. 2002;36(4): Cure rate < 50% 1 –Up to 2 months needed to see improvement Main drawbacks with wet alarm –High noncompliance rate: 30% of patients may discontinue use within 3 weeks 2 –Alarm rings during NREM sleep, the deepest and most difficult time for arousal 3,4 Success highly dependent on motivation of both parents and child 1 Wet Alarm

Most appropriate for older, motivated children > 7 or 8 years of age with motivated families 1 –Wet alarm therapy requires a commitment from other siblings as often all members of the household are wakened when the alarm goes off 2 –Often the family wakes up, not the bed wetter 2 Adapted from Canadian Pediatric Society. Management of primary nocturnal enuresis. Paediatrics & Child Health 2005;10(10): Butler et al. BJU Intern 2002; Vol 89 issue 3; Wet Alarm

The alarm goes off when the child starts to void. It may teach the child to wake up to the alarm and then, by extension, transfer the waking to the sensation of a full bladder 1 Nocturia could replace night time wetting 2 Adapted from Canadian Pediatric Society. Management of primary nocturnal enuresis. Paediatrics & Child Health 2005;10(10): Bonde et al. Scand J Urol Nephrol 1994;28(4): Wet Alarm

Synthetic analogue of ADH Efficacy while treated > 80% 1 –Suitable for children 5 years of age and older 2 –Response to treatment seen within 7 days 2 –Duration: continue for 3 months when the child is dry and stop for one week. Re-initiate at the same dose/duration if needed 2 Adapted from Janknegt et al., Dutch Enuresis Study Group. J Urol 1997;157(2): Ferring Pharmaceuticals, Product Monograph, desmopressin (DDAVP) 2 Desmopressin Acetate

Adapted from Janknegt et al. J Urol 1997;157(2): < 50% reduction wet nights > 50% reduction wet nights > 90% reduction of wet nights Response rate = 84% Clinical Response to Desmopressin 0.2 mg Tablets 1

 In July 2008 Health Canada with support from Ferring, revised the product monograph for all intranasal formulations of desmopressin acetate  Bedwetting treatment indication for both spray & rhinyle are now contraindicated  The central diabetes insipidus indication remains unchanged Adapted from Removal of NE Indication Spray & Rhinyle

Desmopressin spray & rhinyle –Contraindicated for NE 1 Desmopressin tablet 200 µg –Typically requires fluid intake Desmopressin MELT 120 µg and 240 µg –Does not require water –Physiologic activity matches child’s duration of sleep 3 Adapted from eng.php 1 Lottmann et al. Int J Clin Pract 2007; Vande Walle et al. BJU International 2006; 97: 603; Desmopressin Formulations

MELT matches sleep period of children 5+ years of age Hours Melt Tablet Spray Adapted from Product monographs. Vande Walle et al. BJU International 2006; 97:603:309. Average duration of sleep in PNE children Duration of Action

Start with one 120 µg Melt 1 hour before bedtime for 3 nights If not dry, increase by 120 µg Melt every 3 nights to a maximum of 360 µg Melts Treatment should persist as long as symptoms exist Drug holidays every 3 months to evaluate treatment effect Adapted from product monograph Desmopressin acetate (DDAVP) 2008 Dosing Desmopressin Melt

Comparison of Melt and tablet in NE children / adolescents aged 5–15 years 1 Primary result –Melt is statistically significantly preferred by children aged <12 years Secondary results –Efficacy: same number of wet nights –Tolerability: same as tablets –Compliance: improved vs. tablets Adapted from Lottmann et al. Int J Clin Pract 2007, doi: /j x Preference Trial Melt vs. Tablets

p= Melt (n=217)*Tablet (n=218) Episodes/week (mean) Adapted from Lottmann et al., Int J Clin Pract 2007: Efficacy: Number of Wet Nights

No fluid required “Swallowing 57 mL of fluid with a tablet is equivalent to about 25% of the expected bladder capacity of a 7-year- old” 1 Desmopressin Melt eliminates the need for water intake thus reducing an enuretic child’s liquid burden Adapted from Robson WLM, Parkhurst Exchange Desmopressin Melt: No Water

Same efficacy, side effect profile, indication, dosin Matches the average duration of a night sleep in children with PNE No fluid required Preferred by children < 12 years of age Better compliance Eliminates tablet swallowing difficulties Lower dose (120 µg melt =200 µg tab) Desmopressin Melt vs. Tablets

Bedwetting significantly impacts self esteem and instils guilt and shame in childre Bedwetting needs to be diagnosed as part of routine examination Annual physical, routine visits Children and their parents need to be actively involved in the treatment Pearls For Practice

Wet alarm is viable for older, very committed children & highly motivated family –Cure rate < 50% Desmopressin MELT is safe & effective for children of all ages –Lower dose, mimics duration of sleep, no water –Efficacy while treated > 80% Pearls For Practice