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 age1

• Most parents believe that NE is not a physical condition and are uncomfortable initiating a dialogue with physicians1

Adapted from Dunlop et al., Clinical Pediatrics 2005;44:297-303 1.

• Inadequate treatment of NE has psychological ramifications including impaired personal, social and emotional behaviour1,2

– Only parental fighting and divorce are perceived by patients as worse than bedwetting3

Adapted from Fergusson et al. Pediatrics 1986; 78: 884 1 Butler et al. BJU intern 2002; Vol 89; issue 3;295-7 2 Van Tijen et al. British Journal of Urology 1998; 81 Suppl 3:98-9 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 laziness1

– A survey by the Enuresis Resource Information Centre (ERIC) ,UK-based charity

Adapted from http://www.eric.org.uk/Home/tabid/36/Default.aspx 1

Parents’ Perspective

• MDs maintain the notion that patients will outgrow the problem and defer treatment1

• Family Physician residents receive limited training in NE– Not on the curriculum for post graduate students in

the 6 Ontario medical schools2

• Health Canada recently issued a safety bulletin that directly impacts a common treatment option for NE3

Adapted from Gimble et al. Clin Pediatr (Phila). 1998;37(1):23-9 1. Personal communication 2 . http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2008/desmopressin_hpc-cps-eng.php 3

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): 611-4 1

Definition of NE1

Adapted from Fergusson et al., Pediatrics 1986; 78(5):884-90 1 Robson et al. Curr Opin Urol 2008,18;425-30. Klackenberg et al., Acta Paediatr Scand 1981;70:453 3 Yeung et al. BJU Int 2006;97:1069-73.

No

ctu

rnal

Enu

resi

s (%

)

Age (years)

NE resolves spontaneously at a rate of 15% a year2

NE affects twice as many boys than girls3

Prevalence1,4

• Genetic predisposition1

– Family history: one parent 44%, two parents 77%

• Excessive urine production2

– Due to inadequate amount, or response to ADH at night

• Deep sleep and arousal disorder3

– 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):F664-71.2

Wolfish NM. J Urol 2001; 166(6): 2444-7. 3

Etiology

• Diminished functional bladder capacity1

• Slow development of bladder control1

• Emotional and behavioural issues are not causative, but may influence treatment outcome2

Adapted from Wolfish NM. J Urol 2001; 166(6): 2444-7 1

CPS-management of primary nocturnal enuresis (revised Aug 2007)2

Etiology

Urine VolumeUrine VolumeBladder

ContractionsBladder

Contractions

Sleep ArousalSleep

ArousalENURESISENURESIS

Adapted from Wolfish et al., J Urol 2001; Vol. 166, 2444–7.

Causes of Enuresis: A Triad1

Mean variation in urinary excretion rate

ml/h

our

P<0.001

Adapted from Rittig et al. Am J Physiol 1989 Apr;256(4 Pt 2):F664-71.

Circadian Urine Production

Mean variation in plasma antidiuretic hormone (ADH)

P a

vp (

pg/m

l)

P<0.001

Adapted from Rittig et al. Am J Physiol 1989 Apr;256(4 Pt 2):F664-71.

Circadian ADH Production

• Psycho-social impact1,2

– Low self-esteem – Shame, embarrassment– Guilt

• Parents become intolerant of the bedwetting2

• Interferes with age appropriate peer activities1,2

Adapted from Hägglöf et al., Scand J Urol Nephrol 1997;31:533-6. 1

Butler et al, BJU intern 2002; Vol 89 issue 3; 295-7.2

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 night2

– Leads to an overproduction of urine, often more than a child’s small bladder can hold1

• As the children grow, most will eventually stop wetting the bed

Adapted from Butler et al, BJU Intern 2002; Vol 89; issue 3; 295-7 1 Djurhuus et al., Scand J Urol Nephrol Suppl 1992;141:7-17; discussion 18-9 2

NE: It’s NOT the Child’s Fault1

• Screen for NE as most patients are uncomfortable initiating dialogue1

• Investigate history, conduct physical examination and urinalysis2 – 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 2005 1

Canadian Pediatric Society. Management of primary nocturnal enuresis. Paediatrics & Child Health 2005;10(10): 611-4 2

Diagnosis

• Rule out other possible conditions1 – 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;171:2545-61

Diagnosis

• Increase the number of dry nights1 • Minimize the emotional impact of NE1

– 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): 611-4.

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): 611-4 (REVISED AUG 2007)

Common Management Strategies1

• Non-pharmacological – Wet alarm – Behavioural therapy X

• Pharmacological– Desmopressin acetate – Tricyclic antidepressants X /

• extreme caution– Anticholinergics, amphetamine, ephedrine, atropine,

furosemide, diclofenac X

Adapted from Canadian Pediatric Society. Management of primary nocturnal enuresis. Paediatrics & Child Health 2005;10(10): 611-4.

Treatment Approaches1

• Approaches recommended by both the Canadian Paediatric Society1 and the WHO2

– Wet alarm– Desmopressin acetate

Adapted from Canadian Pediatric Society. Management of primary nocturnal enuresis. Paediatrics & Child Health 2005;10(10): 611-4.1

van Gool JD, et al. International Consultation on Incontinence 1998–Monaco; WHO:487-550. 2

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 treatment1

– Treatment modalities require consistent support and cooperation from the child and the family and are unlikely to succeed in their absence2

Adapted from Monda et al, J Urol. 1995 Aug;154:issue 2, 745-8. 1 Tarun Gera et al.,Nocturnal Enuresis In Children. The Internet Journal of Pediatrics and Neonatology. 2001. Volume 2 Number 1.2

Patients Involvement

Adapted from Canadian Paediatric Society Positioning Statement, 2007. 1 Tietjen et al. Mayo Clin Proc 1996;71:857-62. 2 Wolfish et al. J Urol 2001; Vol. 166, 2444–7. 3 Butler RJ et al. Scand J Urol Nephrol. 2002;36(4):268-72. 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 weeks2

– Alarm rings during NREM sleep, the deepest and most difficult time for arousal3,4

• Success highly dependent on motivation of both parents and child1

Wet Alarm

• Most appropriate for older, motivated children > 7 or 8 years of age with motivated families1

– Wet alarm therapy requires a commitment from other siblings as often all members of the household are wakened when the alarm goes off2

– Often the family wakes up, not the bed wetter2

Adapted from Canadian Pediatric Society. Management of primary nocturnal enuresis. Paediatrics & Child Health 2005;10(10): 611-4 .1 Butler et al. BJU Intern 2002; Vol 89 issue 3; 295-7. 2

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 bladder1

• Nocturia could replace night time wetting2

Adapted from Canadian Pediatric Society. Management of primary nocturnal enuresis. Paediatrics & Child Health 2005;10(10):611-4.1 Bonde et al. Scand J Urol Nephrol 1994;28(4):349-52.2

Wet Alarm

• Synthetic analogue of ADH

• Efficacy while treated > 80%1 – Suitable for children 5 years of age and older2

– Response to treatment seen within 7 days2 – Duration: continue for 3 months when the child is dry

and stop for one week. Re-initiate at the same dose/duration if needed2

Adapted from Janknegt et al., Dutch Enuresis Study Group. J Urol 1997;157(2):513-7.1

Ferring Pharmaceuticals, Product Monograph, desmopressin (DDAVP)2

Desmopressin Acetate

Adapted from Janknegt et al. J Urol 1997;157(2):513-7.

< 50% reduction wet nights

> 50% reduction wet nights

> 90% reduction of wet nights

Response rate = 84%

Clinical Response to Desmopressin 0.2 mg Tablets1

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 http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2008/desmopressin_hpc-cps-eng.php

Removal of NE Indication Spray & Rhinyle

• Desmopressin spray & rhinyle– Contraindicated for NE1

• 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 sleep3

Adapted from http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2008/desmopressin_hpc-cps-eng.php 1

Lottmann et al. Int J Clin Pract 2007;1742-1241. 2

Vande Walle et al. BJU International 2006; 97: 603;309.3

Desmopressin Formulations

MELT matches sleep period of children 5+ years of age

Ho

urs

Melt Tablet Spray

Adapted from Product monographs. Vande Walle et al. BJU International 2006; 97:603:309.

Average duration of sleep in PNE children2

7

11

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 years1

• 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: 10.1111/j.1742-1241.01493.x

Preference Trial Melt vs. Tablets

p=0.50

0

0.5

1

1.5

2

2.5

Melt (n=217)* Tablet (n=218)

Ep

iso

des

/wee

k (m

ean

)

Adapted from Lottmann et al., Int J Clin Pract 2007: 1742-124.

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 2007.

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