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Enhancing Bladder Volumes Pharmacologically – Anticholinergics

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 1 Summary Table of Oral Anticholinergics

Author Year

Country
Research Design
Score
Total Sample Size

MethodsOutcome
Propiverine
Stohrer et al. 2013

Germany

RCT

PEDro=7

N=66

Population: Mean age: 41.2 yr; Gender: males=41, females=25; Injury etiology: traumatic (n=35, 57%), stroke (n=15, 23%), inflammable (n=12, 18%), degenerative (n=1, 2%); All individuals had urodynamically-confirmed neurogenic detrusor overactivity.

Intervention: Individuals were randomly allocated to either extended-release (ER, n=33) or immediate-release (IR, n=33) treatment groups: administration of propiverine either in ER capsules (45 mg BID) or coated IR tablets (15 mg TID).

Outcome Measures: Reflex volumes, Maximum detrusor pressure, Leak point volume, incontinence, all were measured at baseline and 21 d after treatment.

Adverse events were assessed as tolerability outcomes.

1.      Reflex volumes improved significantly in both the ER and IR groups, but intergroup differences were non-significant (p<0.0001).

2.      Leak point volume increased and maximum detrusor pressure decreased significantly in both treatment groups, without significant intergroup differences (p<0.0001; p<0.0043).

3.      Incontinence was significantly reduced in the ER group (p<0.0005), and there was a significant intergroup difference.

4.      16 individuals (48%) in the IR group and 12 individuals (36%) in the ER group experienced at least one adverse event.

5.      Treatment related adverse events occurred in 14 individuals (42%) in the IR group and 12 individuals (36%) in the ER group.

6.      Individuals related tolerability of both treatment groups worse in comparison to the investigators.

7.      Post void residual volume increased in both treatment groups.

Stohrer et al. 1999

Germany

RCT
PEDro=9

Initial N=124;

Final N=113

Population: Age range=29-30 yr; Gender: males=69, females=44; All individuals had NDO, suprasacral SCI and used IC for bladder management.

Intervention: 15 mg of propiverine or placebo were given 3x/d for 14 d.

Outcome Measures: Urodynamic parameters, individuals’ clinical symptoms, physician’s assessment of efficacy, adverse events and laboratory parameters (haematology, bleeding times, clinical chemistry etc.)

1.     Significant treatment increases:

·       Bladder capacity (p=0.006).

·       Maximal cystometric bladder capacity (p<0.0001).

·       Residual urine volume (p=0.01).

2.     Significant treatment decreases:

·       Maximal detrusor contractions (p<0.001).

·       Detrusor contraction duration (p<0.03).

3.     Improved clinical symptoms: Treatment=63.3%; placebo=22.6%.

Solifenacin
Chen et al. 2015

China

RCT

PEDro=6

Ninitial=100; Nfinal=98

Population: Neurogenic detrusor overactivity; Mean age: 33.2 yr; Gender: males=91, females=6; Level of injury: cervical=28, thoracic=47, lumbar=23; Severity of injury: complete=75, incomplete=23; Mean time post-injury: 3.4 yr.

Intervention: Individuals were randomized to receive 1) percutaneous tibial nerve stimulation (PTNS group), consisting of surface electrodes placed at the ankle over the course of the tibia nerve for 30 min, 2 times per week, for 4 weeks or 2) solifenacin succinate (SS group), with 5 mg once a day for 4 weeks.

Outcome Measures: Clean intermittent catherization (CIC) frequency, fluid intake, volume per catherization, total leakage volume per day, Incontinence Quality of Life (I-QOL), adverse events.

1.     No significant differences were observed post-treatment and between groups in terms of CIC frequency and fluid intake.

2.     Compared to baseline, the volume per catherization significantly increased (p<0.05), the total leakage volume per day decreased (p<0.05), and the I-QOL significantly improved (p<0.05) for both groups at 2 wk and 4 wk follow-up. However, no significant differences were observed between 2 wk and 4 wk follow-up within groups, or between groups.

3.     No adverse events were reported in PTNS group, compared to 5 participants in SS group reporting dry mouth (2 resulting in study discontinuation).

Krebs et al. 2013

Switzerland

Case Series

N=35

Population: Median age at treatment initiation: 44.9 yr (IQR 34.4 – 56.3 yr); Gender: 25 male, 7 female

Injury Etiology: traumatic (n=30, 85.7%), non-traumatic (n=5,14.3%); Level of injury: complete SCI (ASIA A (N=15)), incomplete (N=20); Level of injury: 4 tetraplegic, 31 paraplegic (91.4% – suprasacral lesions); All individuals had urodynamically confirmed neurogenic detrusor overactivity (NDO).

Intervention: Solifenacin treatment initiated 7.3 yr after SCI (median, IQR 2.7 – 22.0 yr), 33 (94.3%) at 10 mg/d, 2 (5.7%) at 5 mg/d; All procedures were completed between Jan 2008 and Mar 2012

Outcome Measures: Bladder capacity, Detrusor compliance, Maximum detrusor pressure, Reflex volume, Risk of renal damage

1.     At 13.1 mo (median, IQR 6.1–19.5 mo) after treatment, solifenacin treatment significantly improved all urodynamic parameters. Bladder capacity increased by 6% (+30.0 mL (median, IQR 0.0 to 69.0 mL)), detrusor compliance increased by 66% (+25.0 mLcm-1 H2O (median, IQR -1.0 to 50.0 mlcm-1 H2O)), maximum detrusor pressure decreased by 39% (-7.0cm H2O (median, IQR -17.0 to -1.0cm H2O)) and reflex volume increased by 39% (+62.5 mL (median, IQR 12.5 to 101.0 mL)).

2.     Though not statistically significant (p>0.1), fewer individuals presented with a risk of renal damage based on maximum detrusor pressure (6 vs. 13) and detrusor compliance (8 vs. 11), and the majority of individuals (69%) continued solifenacin treatment.

Oxybutynin
Stőhrer et al. 2007

Europe

RCT
PEDro=9

N=131

Population: Mean age: 38.3yr; Gender: males=99, females=32; Injury etiology: Traumatic SCI=122, Myelitis=1, MS=2, Myelodysplasia=4, Spinal tumours=2; All individuals had NDO.

Intervention: To compare the efficacy and tolerability of propiverine and Oxybutynin for individuals with NDO. Individuals were randomized (1:1) to receive 15 mg TID propiverine or 5 mg tid Oxybutynin for 21 d.

Outcome Measures: Maximum cyctometric bladder capacity and bladder pressure.

 

1.     A significant increase was shown in the Max cystometric capacity (mL) for both the propiverine and Oxybutynin treatment groups (198±110 to 309±166 and 164±64 to 298±125, respectively).

2.     A significant decrease was shown in the Max detrusor pressure during the filling phase (cm H20) for both the propiverine and Oxybutynin groups (56.8±36.2 to 37.8±31.6 and 68.6±34.5 to 43.1±29.2, respectively).

3.     During filling cystometry, detrusor compliance showed significant improvements in both groups but no significant inter-group differences resulted.

4.     Residual urine for both groups was increased but the inter-group difference was not significant (p=0.13) (propiverine 72.6 mL±115 to 140.9 mL±167 versus Oxybutynin 65.3 mL±78 to 149 mL±133).

5.     The propiverine group reported less frequent adverse events compared to Oxybutynin (63.0% vs. 77.8%) – Dryness of mouth was most frequently reported (47.1% vs. 67.2% respectively (p=0.02).

Ersoz et al. 2016

Turkey

Pre-Post

N=27

Population: Lower urinary tract dysfunction; Mean age: 35 yr; Gender: males=22, females=5; Level of injury: cervical= 3, thoracic=19, lumbosacral=5; ASIA classification: A=19, B=1, C=6, D=1; Mean time post-injury: 110 d; Injury etiology: traumatic spinal cord injury.

Intervention: Oxybutynin HCl (10 mg/d in 15 cases and 15 mg/d in 12 cases).

Outcome Measures:  Meeting criteria for changing intermittent catheterization (IC) from 6/d to 4/d, maximum cystometric capacity.

1.     At a mean follow-up of 30 d, there were 25 participants that had a maximum cystometric capacity of 400 ml or more, meeting the criteria for changing IC from 6/d to 4/d. Among the 2 cases that did not meet the criteria, one had not taken the medication after meals and one had only increased to 350 ml.

2.     There was a significant increase in maximum cystometric capacity after treatment (p<0.001).

Kennelly et al. 2009

USA

Pre-Post

N=24

Population: SCI individuals with neurogenic detrusor overactivity and incontinence. Mean age: 41.9 yr; Gender: males=21, females=3; Severity of injury: AIS A=17, B=2, C=5.

Intervention: To evaluate the efficacy and safety of Oxybutynin transdermal system (Oxybutynin-TDS) in people with SCI with neurogenic detrusor overactivity and incontinence 8-wk dose titration period, Oxybutynin-TDS doses adjusted every 2 wk.

Outcome Measures: Change in daily number of clean Intermittent catheterization (IC) periods without leakage, from baseline – 8 wk or last observation using 3-d voiding diary, clean intermittent catheterization (IC) volume and urodynamic parameters

1.     Baseline mean daily total clean IC frequency=5.3±1.4

2.     Mean daily number of clean IC periods without leakage=2.4±1.8 (all other were associated with leakage)

3.     During the study, overall mean daily clean IC frequency (observed cases) remained constant

4.     Significant improvements were seen in:

·       Reflex volume (p=0.0466)

·       Maximal cystometric bladder capacity (p=0.0009)

·       Residual urine volume (p=0.0023).

·       Detrusor pressure (p=0.0457).

O’Leary et al. 2003

USA

Pre-Post

N=10

Population: SCI: Age range35-77 yr; Gender: males=2, females=8; Severity of injury: AIS: A-D.

Intervention: Initial 10 mg of Oxybutynin (extended release) daily; increased by 5 mg daily until symptoms were controlled or until a max dosage of 30 mg per d.

Outcome Measures: Micturition frequency diaries and urodynamics were completed at baseline and repeated at wk 12. Tolerability info was also collected.

1.     Mean cystometric bladder capacity volume significantly increased (p=0.008).

2.     Mean number of voids in a 24 hr period decreased (p=0.003).

3.     Residual urine increased (p=0.02).

4.     Nocturia decreased but not by a significant amount.

5.     Incontinence episodes per wk significantly decreased (p=0.03)

Tolterodine
Ethans et al. 2004 Canada

RCT (Tolterodine vs. placebo)

Prospective controlled trial (Oxybutynin vs. tolterodine)
PEDro=6

N=14

Population: Mean age: 40.5 yr; Gender: males=9, females=1; Mean time post-injury=13.7 yr. Injury etiology: SCI, MS.

Intervention: Neurogenic detrusor overactivity tx. Double-blind design with tolterodine (T) 2 mg twice daily vs. placebo (P). Open label: tolterodine self-selected dose (TSSD) vs. Oxybutynin SSD (OSSD).

Outcome Measures: Cystometric capacity, catheterization volumes, number of episodes of urinary incontinence/d, degree of mouth dryness per d using visual analog scale (VAS).

1.     No significant difference between T vs. P groups in:

·       mean cystometric capacity

·       degree of mouth dryness

2.     T vs. P significantly improved:

·       mean catheterization volume (263 mL vs. 188 mL, p<0.001)

·       Number of incontinence episodes/d (1 vs. 2.8, p<0.005)

3.     No significant difference between TSSD vs. OSSD in:

·       mean cystometric capacity

·       catheterization volume

·       number of incontinence episodes/d.

4.     TSSD<OSSD for:

5.     dry mouth (VAS 2.6 vs. 4.4, p<0.05).

Amend et al. 2008

Germany

Prospective Controlled Trial

N=27

Population: SCI individuals with hyperreflexia, Mean age: 35.7yr; Gender: males=21, females=6

Level of injury tetraplegia=15, paraplegia=6.

Intervention: Individuals from a previous study continued treatment in 3 groups: Group A (n=8) received 8 mg of tolterodine and Oxybutynin (15-30 mg); Group B (n=11) received 90 mg of trospium (TCL) and tolterodine (4-8 mg); Group C (n=8) received 30 mg of Oxybutynin and TCL (45-90 mg) for 4 weeks.

Outcome Measures: Incontinence events, bladder capacity, reflex volume, detrusor compliance were all measured at baseline, 4 wk and 6 mo post treatment

1.     No significant difference in outcomes was seen between 4 wk and 6 mo follow up.

2.     Number of incontinence events decreased significantly in all three groups at 4 wk follow up (Group A p<0.001; Group B p<0.0005; Group C p<0.001).

3.     Bladder capacity significantly increased at 4 wk follow up in Groups A (p<0.005), B (p<0.0005), C (p<0.001).

4.     Reflex volume increased in all three groups post 4 wk follow up (Group A p<0.005, Group B p<0.0001, Group C p<0.001).

5.     Detrusor compliance increased after 4 weeks of treatment in Groups A (p<0.005), B (p<0.0001), C (p<0.001)

6.     No significant difference was found among the treatments in detrusor compliance (p=0.97) or incontinence events (p=0.11).

7.     Group A had significantly lower improvement in bladder capacity compared to the other groups (p<0.002).Group C had significantly higher reflex volume than group B.

Horstmann et al. 2006

Germany

Prospective controlled trial

N=21

Population: Mean age:34 yr; Gender: males=15, females=6; Level of injury: paraplegia=7, tetraplegia=10.

Intervention: Individuals were placed into one of two groups: 1) 4 mg of tolterodine once a d; 2) 15 mg of trospium (TCL) 3 times/d. After 4 wk, the dosage was doubled to either 4 mg of tolterodine ER twice/ d or 30 mg of TCL three times/d. Follow-up was monitored by a bladder diary and urodynamic evaluation.

Outcome Measures: Average reflex volume, detrusor pressure, cystometric capacity,

1.     The average reflex volume and cystometric capacity increased significantly (p<0.001).

2.     The maximum detrusor pressure dropped from 60 to 47cm H2O (p<0.05).

3.     Individuals treated with TCL:

·    Average reflex volume increase from 177 to 314 mL (p<0.05)

·    An average cystometric capacity enlargement from 271 to 430 mL (p=0.0005)

·    Maximum detrusor pressure decreased from 66 to 51cm H2O (p<0.05).

4.     Individuals treated with tolterodine:

·    Significant increase was seen in average reflex volume (p<0.05) and bladder capacity (p<0.001).

·    Average maximum detrusor pressure dropped from 54 to 43 cm H2O (p<0.05).

5.     One individual had to stop the medication because of intolerable side effects and five individuals did not experience satisfactory benefits.

Trospium Chloride
Madersbacher et al. 1995

Germany

RCT

PEDro=8

N=95

Population: Trospium chloride (TCL; n=52): Mean age: 32.8 yr (range 16-56); Gender: male=28, females=24; Maximum cystometric bladder capacity: 215.5 mL; Maximum voiding detrusor pressure: 82.1 cmH2O; Compliance: 74.6 mL/cmH2O; Residual urine: 49.2 mL. Oxybutynine (Oxy; n=43): Mean age: 31.3 yr (range 18-54); Gender: male=19, females=24; Maximum cystometric bladder capacity: 185.mL; Maximum voiding detrusor pressure: 82.1 cmH2O; Compliance: 59.5 mL/cmH2O; Residual urine: 48.1 mL; All individuals had NDO.

Intervention: Over a two wk period individuals in the TCL group took TCL (20 mg) twice daily with additional placebo midday. The oxybutynin group took three doses of oxybutynin(5 mg) daily.

Outcome Measures: Maximum bladder capacity, maximum voiding detrusor pressure, bladder compliance, residual urine, hyper-reflexive waves, tolerance variables (dryness of mouth). Urodynamic evaluation taken at baseline and follow-up.

 

1.      Maximum bladder capacity increased significantly in both TCL (215.5 mL to 311.9 mL) and Oxybutynin(187.8 mL to 350.9 mL) treatment groups (p<0.001), the difference between the two treatment groups was not statistically significant (p=0.057).

2.      Maximum detrusor pressure decreased significantly in both treatment groups (p<0.001), difference between the two was not statistically significant (p=0.63).

3.      Bladder compliance significantly increased in the TCL group (74.62 ml/cmH2O to 92.75 ml/cmH2O; p<0.001).

4.      Residual Urine increased significantly in both groups (TCL: 49.2 ml to 128.33 ml; Oxy: 48.14 ml to 154.36 ml) with no significant intergroup differences (p=0.19).

5.      Frequency of hyper-reflexive waves decreased in both groups, with no significant intergroup differences (p=0.16).

6.      Reported severe dryness of mouth was considerably lower in TCL group (4%) compared to the Oxybutyningroup (23%).

7.      Withdrawal from treatment occurred less in those receiving TCL (6%) compared to those receiving Oxybutynin(16%).

Stohrer et al. 1991 Australia

RCT

PEDro=6

N=61

Population: SCI with detrusor hyperreflexia.

Intervention: Trospium chloride (20 mg bid, 3weeks) vs. placebo.

Outcome Measures: Pre-/post-treatment max cystometric capacity (MCC); max detrusor pressure (MDP), urinary flow rate and residual urine volumes, adverse events.

1.     Statistical improvements (p<0.001) in the treatment group vs. placebo:

·  increased MCC

·  decreased MDP

2.     No effect in either group on:

·  max flow rate

·  residual urine volume

·  Side effects low and no difference between groups.

Hadiji et al. 2014

France

Pre-Post

N=231

Population: Neurogenic detrusor overactivity; Mean age=38.4 yr; Gender: males=195, females=36; Level of injury: paraplegia=169, tetraplegia=62; ASIA classification: A=172, B-D=59.

Intervention: Either oxybutynin (15 mg/d) or trospium chloride (40 mg/d) was prescribed as a monotherapy. For those already on an anticholinergic agent, the other drug was added as bitherapy.

Outcomes: Maximum bladder capacity (BCmax), involuntary detrusor contraction (IDC), complete continence.

1.     At a mean follow-up of 1 mo, the mean BCmax significantly increased by 216 mL (p<0.01) and the mean amplitude of IDC significantly decreased by 26 cm H2O (p<0.01).

2.     No significant associations were found between the type of anticholinergic therapy (mono- or bi-therapy) and urodynamic balance.

3.     Only 75 (32%) of participants were fully continent at a mean follow-up of 1 mo.

Cisapride (FDA removal from market on July 14, 2000).
Wyndaele & Kerrebroeck 1995

Belgium

RCT

PEDro=5

N=21

Population: Mean age: 32 yr (range 17 -59); Gender: males=17, females=4; Etiology of SCI: traumatic (n=18, 86%), medical cause (n=3, 14%). All individuals had complete SCI and were out of spinal shock for 1.5 mo before entering the study.

Intervention: Individuals were randomly allocated to receive cisapride or a placebo for 4 wk. Cystometry was performed at baseline and during the testing period.

Outcome Measures: Maximum cystometric capacity, Volume at the first sensation of filling, Volume at the sensation to void, Maximum detrusor pressure, Compliance, Bladder Capacity at the first involuntary detrusor contraction, and Residual volume.

1.      There were no significant differences in urodynamic parameters between baseline and the end of the study in either group, nor were there any differences found in any of the parameters between groups.
Imidafenacin
Sugiyama et al. 2017

Japan

Case Series

N=34

Population: Mean age=60±15yr; Gender: males=29; females=5; Etiology: SCI=34; Time since injury=102±45d; Inclusion criteria: SCI with low cystometric volume and/or detrusor compliance.

Intervention: Individuals were administered 0.2mg imidafenacin/d. If cystometric capacity and/or detrusor compliance remained low at first follow-up (4 wk), dosage was escalated to 0.4mg imidafenacin/d. Individuals managed their bladders with transurethral catheters during the treatment period. Outcome measures were assessed at baseline, 4 wk, and 8 wk.

Outcome Measures: Bladder capacity; detrusor compliance; maximum detrusor pressure.

1.     There was a significant increase in bladder capacity and compliance post-imidafenacin (p=0.002; p=0.012)

2.      Imidafenacin had no effect on maximum detrusor pressure (p>0.05).

Note: AIS=ASIA Impairment Scale

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.