+100%-

Anticholinergic Therapy for SCI-Related Detrusor Overactivity

Download as a PDF

The body of the detrusor is comprised of smooth muscle that contains muscarinic receptors which bind acetylcholine and initiate muscle contractions. Therefore, muscarinic anticholinergics can therefore inhibit detrusor contractions and increase detrusor relaxation (compliance), thereby facilitating higher volumes during filling under lower pressure. Available medications for overactive bladder in this class include oxybutynin (available as Ditropan, Ditropal XL, Oxytrol, Uromax, etc), tolterodine (available as Detrol, Detrol LA), fesoterodine (marketed as Toviaz), trospium chloride (TCL, Trosec), propiverine hydrochloride (Mictonorm) and M3-receptor specific medications darifenacin (Enablex) and solifenacin (Vesicare).

Table: Summary Table of Oral Anticholinergics

Discussion

While 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 three times 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 (a goal in those on intermittent catheterizations) 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 long-acting option is daily oral solifenacin. Solifenacin is an oral antimuscarinic drug that is thought to selectively bind to the bladder’s muscarinic (M) 3 receptors responsible for contraction of the detrusor. Krebs et al. (2013) conducted a retrospective analysis of case histories and urodynamic data of 35 SCI individuals over a four 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 is an anticholinergic agent used extensively and clinically to treat overactive bladder, yet relatively few studies have been performed in the neurogenic bladder population with this medication. Longer acting versions of oxybutynin in forms have sparked renewed research interest with the hopes of reducing side effects observed with the short acting oxybutynin. In a small (n=10) pre-post trial, O’Leary et al. (2003) showed that controlled-release oxybutynin was efficacious for individuals with SCI and detrusor hyperreflexia as reflected by significantly increased bladder volumes with a decrease in mean number of voids per 24 hours. However, post-void residual volumes, nocturia, and weekly incontinence episodes did not change significantly. In a larger 2016 pre-post trial (Ersoz et al 2016, n=27), sub-acute individuals were able to reduce ICs from 6 to 4 per day, by achieving a maximum cystometric capacity of 400 ml or more with compliant oxybutynin administration.  However, Hadiji et al (2014, pre-post study, n=231) caution that oxybutynin (no difference between use as mono- or bi-therapy) only allows full continence in about 32% of individuals despite being effective in raising maximum bladder capacity and decreasing involuntary detrusor contractions.

Oxybutynin use is unfortunately accompanied by many dose limiting side effects (e.g. dry mouth) (del Popolo G et al 2012) and therefore non-pharmacological treatments for NDO are an area of active interest.  Surface percutaneous tibial nerve stimulation of L4-S3 fibres (originating from the same spinal segments as bladder and pelvic floor innervations) has been shown to be as effective as oxybutynin for the treatment of NDO but without the aforementioned side effects. (Chen G et al 2015; RCT, N=100). For individuals who are refractory to oxybutynin or opposed to pharmacological treatments, twice weekly neuromodulatory sessions (30 minutes each) managed at home may be a feasible alternative to pharmacological treatment of NDO.

Tolterodine

Tolterodine, a newer anticholinergic that causes less dry mouth compared to oxybutynin, 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 compared to placebo (Ethans et al. 2004). This trial was small, and thus at risk for type 2 error. As part of the eligibility criteria for this study, subjects were using oxybutynin 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 oxybutynin and tolterodine. The two drugs were found to be equivalent 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 trospium chloride, 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) for individuals with SCI and 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 few 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 oxybutynin (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 the 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 individuals treated with TCL withdrew from the study (6% versus 16%).

Comparisons

Additional investigations have compared 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 similar efficacy in a comparative study of propiverine versus oxybutynin 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 / oxybutynin, 2) TCL/tolterodine or 3) oxybutynin /TCL and demonstrated that 85% of individuals 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 effects on cardiac rhythm when administering doses of combinatorial anti-cholinergics. However, neither study reported conducting an electrocardiogram; therefore concerns for potential cardiac abnormalities in those on combination treatment may need further consideration and investigation.

In addition, Kennelly et al. (2009; n=24) reported that transdermal oxybutinin was effective in increasing the proportion of individuals performing 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.

Imidafenacin

Imidafenacin is an anticholingeric that does not target the salivary glands (Sugiyama et al., 2017). Imidafenacin is selective for the bladder and has been reported to a lower incidence of constipation compared to other new anticholinergics (Sugiyama et al., 2017). In a retrospective chart review authors investigated 34 SCI individuals prescribed imidafenacin due to low cystometric volume and/or detrusor compliance. The authors found a significant increase in bladder capacity and compliance, but no effect on maximum detrusor pressure post-treatment (Sugiyama et al., 2017).

Conclusion

There is level 1a evidence (from three RCTs; Stohrer et al. 1999; Stohrer et al. 2007; Stohrer et al. 2013) that 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 1b 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) suggesting 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 1b 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 individuals with neurogenic detrusor overactivity except that tolterodine results in less dry mouth.

There is level 1b evidence (from an RCT; Chen et al. 2015) that CIC frequency and total leakage volume per day decreased while catheterization volume increased equivocally with oxybutynin administration or percutaneous tibial nerve stimulation (PTNS) where problematic side effects of oxybutynin were not reported in the PTNS group.

There is level 4 evidence (from pre-post studies; O’Leary et al. 2003; Kennelly et al. 2009; Hadiji et al 2014; Ersoz et al 2016) that supports the potential benefits of oxybutinin administration (oral, controlled-release or transdermal), with transdermal administration resulting in a reduced side effect profile.

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

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

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

  • Combinatorial treatment with 2 of oxybutynin, tolterodine or trospium may be effective for the treatment of neurogenic bladder in individuals with SCI who have not previously responded to one medication.

  • Tolterodine, propiverine (particularly the extended-release formula), or transdermal oxybutynin likely result in less dry mouth but have similar efficacy to oral oxybutynin in terms of improving neurogenic detrusor overactivity.