AA

Anticholinergic Therapy for SCI-Related Detrusor Overactivity

The body of the detrusor is comprised of smooth muscle that contains muscarinic receptors triggered by acetylcholine to cause muscle contraction. Therefore, to relax the detrusor and allow it to fill with higher volumes under lower pressure, anticholinergics may be used. Common marketed medications in this class used for overactive bladder include oxybutynin (available as Ditropan, Ditropal XL, Oxytrol, Uromax, etc), tolterodine (available as Detrol, Detrol LA), fesoterodine (marketed as Toviaz), and more recently, trospium chloride (TCL, Trosec), propiverine hydrochloride (Mictonorm) and M3-receptor specific medications darifenacin (Enablex) and solifenacin (Vesicare).

Table: Summary Table of Oral Anticholinergics

Discussion

Although there are numerous anticholinergics available for use in overactive bladder, few have been tested in clinical trials for people with SCI and neurogenic detrusor overactivity (NDO). Only those that have been trialed for SCI-related neurogenic bladder are presented here.

Propiverine

Propiverine has both anticholinergic and calcium channel blocking properties, thus decreasing involuntary smooth muscle contractions. In the SCI population, a double-blind, placebo-controlled, randomized, multicentre (n=124 with 113 completers) study, utilizing 15 mg thrice daily administration of propiverine over two weeks yielded significant improvement in SCI detrusor hyperreflexia represented by increased maximal cystometric bladder capacity (Stohrer et al. 1999). A subsequent increase in residual urine volume was found, as is the goal in those on concurrent IC. Side effects (primarily dry mouth) were considered tolerable.

Two propiverine hydrochloride formulations, extended-release versus immediate-release (ER: 45 mg daily versus IR 15 mg thrice daily), proved to be equally effective in 65 people with SCI with proven NDO. This double-blind, randomized, multicenter study (Stohrer et al. 2013) also presented data to demonstrate higher continence and tolerance rates for the ER formulation.

Solifenacin

Another extended-release option, for the treatment of NDO secondary to SCI, is daily oral solifenacin. Solifenacin is an oral antimuscarinic drug that is thought to selectively bind to the bladder’s M3 muscarinic receptors responsible for contraction of the detrusor. Krebs et al. (2013) conducted a retrospective analysis of case histories and urodynamic data of 35 SCI patients over a 4 year span. Data supporting significantly improved bladder capacity, detrusor compliance, reflex volume and maximum detrusor pressure were reported after an average of 13.1 months of solifenacin treatment.

Oxybutynin

Oxybutynin (OXY) is an anticholinergic agent used extensively and clinically to treat overactive bladder, yet few studies have been performed on the neurogenic bladder population with this medication. Newer versions of OXY in longer acting forms have sparked renewed research interest with the hopes of reducing side effects observed with the short acting OXY. O’Leary et al. (2003), in a small (n=10) pre-post trial showed that controlled-release OXY was efficacious for SCI individuals with detrusor hyperreflexia as reflected by significantly increased bladder volume with decreased mean number of voids per 24 hours. However, post-void residual volumes, nocturia, and weekly incontinence episodes did not change significantly.

Tolterodine

Although OXY is commonly chosen to treat overactive bladder, it is accompanied by bothersome side effects such as dry mouth. A newer anticholinergic that causes less dry mouth, tolterodine, has also been shown to be efficacious for the treatment of neurogenic bladder dysfunction. In a randomized controlled trial (RCT), use of tolterodine was shown to result in significantly increased IC volumes (p<0.0005) and reduced incontinence (p<0.001) but was similar in its effects on cystometric bladder capacity when compared to placebo (Ethans et al. 2004). This trial was small, thus at risk for type 2 error (i.e. failing to detect an effect that is present). As part of the eligibility criteria for this study, subjects were using OXY and IC prior to a 4-day washout in advance of randomization to the tolterodine versus placebo study. This design allowed for a comparison between OXY and tolterodine. The two drugs were found to be equivocal with respect to effectiveness as reflected in IC volumes, degree of incontinence and bladder capacity. Horstmann (2006) found that compared to baseline tolterodine improved reflex volumes, cystometric capacity, and maximum detrusor pressures. Although this study also evaluated TCL, the two medications were only evaluated in a pre-post manner rather than a head to head comparison.

Trospium Chloride

Trospium chloride (TCL; an anticholinergic medication that is reported not to cross the blood-brain barrier) has only recently been approved in North America for use in overactive bladder, where as it has been available in Europe for many years. The efficacy of TCL (20mg bid) in SCI with detrusor hyperreflexia was confirmed by Stohrer et al. (1991) in a RCT. Highly significant (p<0.001) responses were found in favour of TCL versus placebo for increased bladder capacity and compliance, and decreased bladder pressure with low side effects. No effect was reported for flow rate and residual urine volumes. Horstmann et al. (2006) found that TCL improved reflex volume, cystometric capacity, and maximum detrusor pressure. Presumably the psychometrically measured cognitive changes seen with medications such as oxybutinin are not seen with TCL as it does not cross the blood brain barrier. However, psychometric testing has not been examined specifically in persons with SCI taking TCL.

In a randomized, double-blind, multicenter trial directly comparing TCL (20 mg bid) versus OXY (5 mg tid) for 2 weeks in the treatment of detrusor hyperreflexia in 95 individuals with SCI, objective urodynamic parameters (maximum bladder capacity and maximum voiding detrusor pressure during micturition) showed that that two medications were equally efficacious (Madersbacher et al. 1995). However, TCL emerged superior with respect to fewer reports of severe dry mouth (4% versus 23%) and subsequently fewer patients treated with TCL withdrew from the study (6% versus 16%).

Comparisons

More recent investigations have been conducted to provide comparison information about the relative efficacy and presence of side effects associated with various anticholinergic drugs (Amend et al. 2008; Stohrer et al. 2007). Stohrer et al. (2007) showed similarities in efficacy in a comparison study of propiverine versus OXY that employed a double-blind, RCT design. Both treatments significantly improved bladder capacity and reduced maximum detrusor pressure although fewer side effects (most notably dry mouth) were evident in subjects in the propiverine group. Of note, Amend et al. (2008) examined 3 combinations of anti-cholinergics in 27 subjects whose symptoms of incontinence did not completely resolve with an initial treatment option – even with dosages doubled from manufacturer recommendations (i.e., Horstmann et al. 2006). These authors added a second anti-cholinergic medication such that participants took either: 1) tolterodine/OXY, 2) TCL/tolterodine or 3) OXY/TCL and demonstrated that 85% of patients were treated successfully with a combination treatment option, despite having mostly unsatisfactory outcomes with a single medication. Each initial medication was maintained at the high dose (i.e., double dose) and there were no clear combinations that were superior to the other in terms of either effectiveness or side effect profile. It should be noted that there is a concern for potential consequences on heart rhythm when administering doses of mixed anti-cholinergics. However, neither study reported conducting an electrocardiogram and therefore concerns about potential cardiac abnormalities incurred by those receiving a combination treatment may need further consideration and investigation.

In addition, Kennelly et al. (2009; n=24) reported that a transdermal method of oxybutinin was effective in increasing the proportion of clean IC without leaking, as well as improving various urodynamic measures (e.g., reflex volume, amplitude of detrusor contraction, maximum bladder capacity, residual urine volume) in a pre-post investigation. Along with these positive effects there were, more importantly, fewer side effects than typically reported with oral delivery, even at up to three times the standard dose.

The acetylcholine blocking property of anticholinergics and their effectiveness on treatment of overactive bladder was indirectly established through the double-blind, placebo controlled study of cisapride, which facilitates acetylcholine delivery to effect smooth muscle motility, and its effect on cystometric parameters in SCI patients (Wyndaele & Van Kerrebroeck, 1995; n=21). No significant difference in pre- and post- (4 weeks at 10mg oral four times daily) urodynamic parameters in both active and placebo groups represents level 6 evidence that puts to rest earlier claims (5 small level 4 and 5 studies from the early 1980s and 1990s) that advocated the use of cisapride in spinal cord injured people with hyperreflexic bladders. Wyndaele and Van Kerrebroeck did report some variable positive effects of cisapride (but not placebo) when cystometric parameters (max capacity and at first contraction, detrusor pressure, compliance, and residual urine) were observed individually, but the clear influence of cisapride was not apparent.  

Conclusion

There is level 1a evidence (from three RCTs; Stohrer et al. 1999; Stohrer et al. 2007; Stohrer et al. 2013) supports the use of propiverine in the treatment of detrusor hyperreflexia resulting in significantly improved bladder capacity, with one of these trials showing equivalent results to oxybutinin but fewer side effects, notably dry mouth.

There is level 1 evidence (from a single RCT; Stohrer et al. 2013) that demonstrated superiority for continence and tolerability when propiverine extended-release is compared to immediate release formulations.

There is level 4 evidence (from a single case series; Krebs et al. 2013) suggested that solifenancin id (10 or 5 mg) is effective in improving bladder capacity, detrusor compliance, reflex volume and maximum detrusor pressure in individuals with neurogenic detrusor overactivity secondary to SCI.

There is level 1 evidence (from a single RCT Ethans et al. 2004) that supports the use of tolterodine versus placebo to significantly increase intermittent catheterization volumes and decrease incontinence in neurogenic detrusor overactivity.

There is level 2 evidence (from a prospective controlled trial; Ethans et al. 2004) that tolterodine and oxybutynin are equally efficacious in SCI patients with neurogenic detrusor overactivity except that tolterodine results in less dry mouth.

There is level 4 evidence (from pre-post studies; O’Leary et al. 2003; Kennelly et al. 2009) that supports the potential benefits of controlled-release oxybutynin as well as a transdermal system for oxybutinin administration, the latter with a reduced side effect profile.

There is level 4 evidence (from a prospective controlled trial; Amend et al. 2008) that suggests benefits such as reduced incontinence and increased bladder capacity from combination treatments of two of oxybutinin, trospium chloride or tolterodine, even in patients with unsatisfactory outcomes following a trial with one of these medications.

There is level 1a evidence (from two RCTs; Stohrer et al. 1991; Madersbacher et al. 1995) that support the use of trospium chloride to increase bladder capacity and compliance, and decrease bladder pressure with very few side effects in SCI individuals with neurogenic bladder.

There is level 1b evidence (from one RCT; Wyndaele & Van Kerrebroeck 1995) that demonstrates that cisapride is not clearly effective in the treatment of hyperreflexic bladders in individuals with SCI.

  • Propiverine, oxybutynin, tolterodine and trospium chloride are efficacious anticholinergic agents for the treatment of SCI neurogenic bladder.

    Treatment with 2 of oxybutynin, tolterodine or trospium may be effective for the treatment of SCI neurogenic bladder in those not previously responding to one of these medications.

    Tolterodine, propiverine (particularly the extended-release formula), or transdermal application of oxybutinin likely result in less dry mouth but are similarly efficacious to oral oxybutynin in terms of improving neurogenic detrusor overactivity.

    Cisapride is not an effective treatment for hyperreflexic bladders in individuals with SCI.