SEARCH

SEARCH BY CITATION

INTRODUCTION

  1. Top of page
  2. INTRODUCTION
  3. NEW DEVELOPMENTS IN AETIOLOGY OF DETRUSOR DYSFUNCTION
  4. TARGETS FOR TREATMENT OF DETRUSOR OVERACTIVITY
  5. CONCLUSIONS
  6. CONFLICTING INTERESTS
  7. References

The treatment of detrusor overactivity or overactive bladder has relied on a single approach; namely bladder retraining and broad spectrum anticholinergic medication. The results of treatment are often disappointing due to the poor compliance and marked side-effects. However, over the last 10 years with increasing recognition of the importance of quality of life improvement and improvement in a patients' wellbeing, rather than simply the absence of disease, further pharmacological therapies have been developed. Although the mechanism of actions of these agents is very similar the side-effect profiles are better. Newer agents with more novel sites of action are also under investigation and may lead to new therapies for this condition, which is difficult to treat and has greater impact on quality of life than many other chronic health problems (Table 1).

Table 1.  Common anticholinergic side-effects.
Common anticholinergic side-effects
Dry mouth
Constipation
Palpitations
Heart burn
Blurred vision
Nausea
Facial flushing

NEW DEVELOPMENTS IN AETIOLOGY OF DETRUSOR DYSFUNCTION

  1. Top of page
  2. INTRODUCTION
  3. NEW DEVELOPMENTS IN AETIOLOGY OF DETRUSOR DYSFUNCTION
  4. TARGETS FOR TREATMENT OF DETRUSOR OVERACTIVITY
  5. CONCLUSIONS
  6. CONFLICTING INTERESTS
  7. References

Control of the storage, voiding function of the bladder is one of the most complex functions of the autonomic nervous system. Regulation of the bladder requires the correct co-ordination between the bladder and the integrity of the afferent and efferent spinal tracts with the higher micturition centres orchestrated by the pontine micturition centre. The control relies on both the traditional autonomic and the somatic supplies. A third group of fibres termed nonadrenergic noncholinergic (NANC) fibres have been identified. These nerves are classified as ‘purinergic’ because they rely on purines as neurotransmitters, the most common of which is ATP.1 In the bladder NANC fibres are found in higher concentration with increasing age, and in conditions such as interstitial cystitis and neurogenic detrusor overactivity.

TARGETS FOR TREATMENT OF DETRUSOR OVERACTIVITY

  1. Top of page
  2. INTRODUCTION
  3. NEW DEVELOPMENTS IN AETIOLOGY OF DETRUSOR DYSFUNCTION
  4. TARGETS FOR TREATMENT OF DETRUSOR OVERACTIVITY
  5. CONCLUSIONS
  6. CONFLICTING INTERESTS
  7. References

Traditional approaches to detrusor overactivity have been based on pharmacological manipulation of acetyl choline as the neurotransmitter responsible for stimulating a detrusor contraction via muscarinic receptors. There are five identified subtypes of muscarinic receptors within the parasympathetic system. M2 is the most common receptor within the bladder but it is the M3 receptor that is probably the more pharmacologically active receptor in detrusor activity, differing from M2 by the second messenger system. Andersson and Yossihida2 have demonstrated that in usually prescribed doses, anticholinergic medications will act predominately on the storage function of the bladder and not the voiding function explaining why retention is a relatively rare occurrence. This effect is mediated by acetylcholine released by the bladder wall in response to bladder wall stretching as part of the reflex arc of bladder emptying seen in babies and spinal transaction patients.

Over the last 10 years much research has been aimed at improving the target end-organ specificity to reduce unwanted side-effects of anticholinergic medications. Unfortunately the most predominant side-effect, that of a dry mouth, is also caused by blockade of the muscarinic receptor in the salivary glands. Hence why the first M3 specific medication oxybutynin, although a good therapeutic agent with proven efficacy,3 is not associated with a significantly better patient compliance compared with tricyclic antidepressants and propantheline bromide. The introduction of a controlled release preparation that reduces peak serum levels of oxybutynin and its highly active metabolite N-desethyloxybutynin has led to a reduction in the reported incidence and severity of the anticholinergic side-effects; without losing the efficacy of intermittent release preparations.4 Next year will see the launch of an oxybutynin skin patch that bypasses the enterohepatic metabolism and therefore results in much lower production of N-desethyloxybutynin. Early trials have show equal efficacy as the intermittent release or controlled release preparation but with much reduced side-effects.5

Tolterodine tartrate was derived from terodoline. This antimuscarinic molecule displays a far greater affinity for the bladder compared with other end organs and as a consequence is associated with an improved side-effect profile similar to the slow release preparation of oxybutynin. Multiple studies have demonstrated that tolterodine is more effective than placebo, equally efficacious as oxybutynin with a better side-effect profile.6,7 The once-daily controlled release preparation may lead to better treatment compliance.

The last 3 years have also seen the introduction of a new anticholinergic, trospium chloride. This alkaloid was first discovered in the late 1960s and has seen increased usage levels in Europe prior to its launch in the UK. The potential advantages of trospium chloride, whilst it has broad spectrum effects, include its relative inertness leading to a high excretion rate unmetabolised in urine where it may have a local effect (thus reducing systemic side-effects) and its theoretical low permeability across the blood–brain barrier therefore causing less cognitive impairment. A recent large multicentre, randomised trial has shown trospium to be significantly more effective than placebo.8

Propiverine chloride is an anticholinergic that is available as an immediate release preparation and is more effective than placebo for symptoms of overactive bladder. An extended release preparation has similar efficacy and side-effects as the immediate release.9

Solifenacin succinate, a new bladder selective antimuscarinic agent suitable for once-daily administration, is also due for launch this year. In a randomised trial versus tolterodine, 5 mg once-daily of solfenacin produced a similar reduction in the symptoms of overactive bladder with a lower incidence of side-effects.10 Its clinical utility will be assessed after launch but it is an addition that should be useful in our armamentarium.

Darifenacin, a new M3 selective agent, has also shown promising results versus placebo and further trials are underway.11

The use of anticholinergics alone, however, has always been less than satisfactory as the medications do little to modulate the underlying pathophysiology of the bladder. This has been encapsulated in the conclusion of a meta-analysis by Herbison et al.,12 which states: ‘although statistically significant the differences between anticholinergics and placebo were small…of questionable clinical significance’, whilst this paper drew a lot of criticism it perhaps does highlight a number of points. The use of an anticholinergic should only be considered as part of a package of treatment that should be tailored to the individual. If this is the case then perhaps the trend by the pharmaceutical companies to try and encourage prescribing on symptoms alone, without investigation and without referral for behavioural therapy needs to be questioned.

The treatment package for patients with detrusor overactivity or urge syndrome (depending on whether treating by diagnosis from urodynamics or by symptoms alone) must encompass behavioural therapy. This encompasses lifestyle changes, physical changes and bladder retraining,13 which will require increased resources in terms of continence advisors and interested physiotherapists in conservative therapy.

A further area of potential improvement in current treatments has been the increasing interest in polypharmacy with the use of more than one medication which may be synergistic. This has led to an increase in the prescribing of many of the ‘older’ treatments such as tricyclic antidepressants to augment more ‘modern’ anticholinergics with imipramine being used at night for its longer action and amityptyline in patients with bladder pain (often with oxybutynin, which has local anaesthetic effects). Used in low doses (25–50 mg) there is little chance of behavioural disturbance by addiction, which might be associated with higher doses.

The search for other modalities of treatment has continued due to the relatively poor response to anticholinergics in terms of long-term cure. However, topical oestrogen therapy may be an important consideration particularly in the elderly.

Desmopressin is a synthetic analogue of antidiuretic hormone and is available as a nasal spray and oral preparation. It is licensed as the first-line treatment for paediatric nocturnal enuresis. However, its use in adults has been disappointing due to the relatively frequent occurrence of side-effects related to fluid retention and hyponatraemia. There is some evidence that it may be used as a ‘designer’ drug in the day time with the patient using the medication on a prn basis, as long as the usage is not frequent there is unlikely to be any significant metabolic disturbance and the need for regular review and electrolyte testing may be removed.14 The exact role and dosage that is acceptable has yet to be defined.

In view of the fact that the majority of traditional medications described above work by a similar (anticholinergic) mechanism, there has been a lot of interest in exploring other potential sites of action of medication to expand the armamentarium of treatment. This area of interest has been investigated particularly in patients with neuropathic detrusor overactivity who present unique problems, particularly the risk of upper tract damage leading to renal impairment.

There have been many publications looking at the use of capsaicin, which is the active ingredient in chilli peppers. The action of capsaicin is to deplete substance P, the neurotransmitter in the pain C-fibres. The effect of treatment with capsaicin is to decrease the micturition reflex and hence increase the first desire to void. It's main advantage, however, is to modulate/decrease pain fibres. Its administration is intravesical and its use generally limited to MS and spinal cord transection patients. The limitations of capsaicin are the route of administration and pain whilst ‘burning out’ the P receptors.

Resiniferatoxin, a substance isolated from a cactus, has been found to be 1000 times more potent and hence more effective as the effect on the pain fibres is much faster, allowing less stimulation prior to ‘burn out’. However, its clinical effectiveness has yet to be confirmed.

Botox (Botulinum toxin) acts by partial (or total) paralysis of the detrusor muscle after direct injection at multiple sites. In early studies of patients with detrusor overactivity refractive to other treatments, there are encouraging reports of benefit with minimal side-effects.15 There may be the need for repeated injections and to date there is a paucity of long-term data available. Hopefully with increased usage the unit cost of Botox will also decrease, as at current the cost may prove prohibitive.

A further possible treatment modality will be Duloxetine, a novel SNRI medication. This preparation is due to be launched later this year with a license for stress incontinence. Its principle mode of action is at a spinal level through modulation of Onuf's nucleus, where it acts to increase stimulation of the urethral striated sphincter muscle. However, there is some evidence to suggest that it may in addition have effects modulating overactive bladder symptoms.

Two further potential pharmacological sites will require the development of novel agents. The first group of agents is potassium channel agonists, which act by modulating the membrane potential to increase potassium efflux, which modulates the voltage regulated calcium channels in the detrusor muscle. There are currently two types that have been identified, firstly ATP sensitive and secondly calcium activated. Whilst these offer a potentially exciting mode of treatment, their usage will be predominantly in symptom control (as with the anticholinergic medications) but they may offer an alternative to anticholinergics. These are currently undergoing phase II trials. Finally there are the purinergic receptors, which are being recognised as an increasingly important mediator of the disease process in the overactive bladder. The predominant receptor appears to be the P2X receptor in smooth muscle with the P4 receptors being another potential site of action centrally.

The final advance in detrusor activity has been the development of neuromodualtion of the sacral nerve routes. This involves the placement of a temporary pacing wire into the sacral foramina to check patient response. If the patient responds to the temporary pacing then a permanent stimulator can be implanted. It can be effective for overactive bladder symptoms as well as voiding dysfunction. While it can be considered for some patients where conservative measures have failed, the cost of a permanent implant may be prohibitive to many units with a cost of approximately £6000.

CONCLUSIONS

  1. Top of page
  2. INTRODUCTION
  3. NEW DEVELOPMENTS IN AETIOLOGY OF DETRUSOR DYSFUNCTION
  4. TARGETS FOR TREATMENT OF DETRUSOR OVERACTIVITY
  5. CONCLUSIONS
  6. CONFLICTING INTERESTS
  7. References

There has been an increase in the number of treatments available for detrusor overactivity over the last 10 years. However, the mode of action has always been based on anticholinergic effects to ‘modulate’ bladder function rather than ‘cure’. The future is exciting as the development of an increasing diversity of pharmacological sites leads to an increasing treatment range. Hopefully this will increase the percentage of patients who respond to treatment as the side-effect profiles will vary. Treatment undoubtedly will continue to require behavioural therapy to underpin the changes established by pharmacological modulation.

CONFLICTING INTERESTS

  1. Top of page
  2. INTRODUCTION
  3. NEW DEVELOPMENTS IN AETIOLOGY OF DETRUSOR DYSFUNCTION
  4. TARGETS FOR TREATMENT OF DETRUSOR OVERACTIVITY
  5. CONCLUSIONS
  6. CONFLICTING INTERESTS
  7. References

Philip Toozs-Hobson has undertaken industry sponsored research or consultancy for Pharmacia (now part of Pfizer), Ely-Lily, Galen & Maudus, Apophogepha and Astra-Zeneca.

References

  1. Top of page
  2. INTRODUCTION
  3. NEW DEVELOPMENTS IN AETIOLOGY OF DETRUSOR DYSFUNCTION
  4. TARGETS FOR TREATMENT OF DETRUSOR OVERACTIVITY
  5. CONCLUSIONS
  6. CONFLICTING INTERESTS
  7. References
  • 1
    Andersson K-E. Pharmacology of lower urinary tract smooth muscles and penile erectile tissues. Pharmacol Rev 1993;45:253.
  • 2
    Anderson K-E, Yoshida M. Antimuscarinics and the overactive bladder — which is the main mechanism of action? Eurpoean Urol 2003;1:15.DOI: 10.1016/S0302-2838(02)00540-7
  • 3
    Cardozo LD, Cooper D, Versi E. Oxybutynin chloride in the management of idiopathic detrusor instability. BMJ 1987;280:281282.
  • 4
    Birns J, Malone-Lee JG, and the oxybutynin CR Study Group. Controlled-release oxybutynin maintains efficacy with a 43% reduction in side effects compared to conventional treatment. Neurourol Urodyn 1997;16:429430.
  • 5
    Dmchowski R, Staskin D, Appell R, et al. The efficacy, effectiveness, and safety of transdermal oxybutynin in patients with overactive bladder. Neurourol Urodyn 2003;22:533534.
  • 6
    Abrams P, Freeman RM, Anderstrom C, Mattiasson A. Efficacy and tolerability of tolterodine vs oxybutynin and placebo in patients with detrusor instability. Br J Urol 1998;81:801810.DOI: 10.1046/j.1464-410X.1998.00717.x
  • 7
    Van Kerrebroeck PEVA, Serment G, Dreher E. Clinical efficacy and safety of tolterodine compared to oxybutynin in patients with overactive bladder. Neurourol Urodyn 1997;16:478479.
  • 8
    Rudy D, Cline K, Goldberg K, Harris R. A multicenter randomized, placebo controlled trial of trospium chloride in overactive bladder patients. Neuurol Urodyn 2004;23:600601.
  • 9
    Juenemann K, Hessdoerfer E, Unamba-Oparah I, et al. Propiverine Hydrochloride immediate (IR) and extended release (ER): comparison of efficacy and tolerability in patients with overactive bladder. Neurourol Urodyn 2004;23:599600.
  • 10
    Chapple C, Rechberger T, Al-Shukri S, Meffan P, Everaert K, Ridder A. Results of a randomized phase 3 study comparing solifenacin succinate with tolterodine and placebo in patients with symptomatic overactive bladder. Neurourol Urodyn 2003;22:534535.
  • 11
    Hill S, Khullar V. Darifenacin, a muscarinic receptor antagonist with selectivity for M3 receptors, reduces incontinence and nocturia in patients with overactive bladder. Neurourol Urodyn 2004;23:602603.
  • 12
    Herbison P, Hay-Smith J, Moore K. Effectiveness of anticholinergic drugs compared with placebo in the treatment of overactive bladder: systematic review. BMJ 2003;326:841844.
  • 13
    Wilson D. Nonsurgical management of incontinence. In: MacleanAB, CardozoLD, editors. Incontinence in Women. RCOG Press, 2002 Chapter 16.
  • 14
    Robinson D, Cardozo L, Akeson M, Hvistendhal G, Riis A, Norgaard JP. Anti-diuresis—for the control of daytime incontinence. Int Urogynecol J 2002;13:S6.
  • 15
    Leippold T, Reitz A, Schurch B. Botulinum toxin as a new therapy for voiding disorders: current state of the art. Eur Urol 2003;44:165174.DOI: 10.1016/S0302-2838(03)00250-1