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Alpha-adrenergic Blockers for Bladder Emptying

A variety of alpha-adrenergic blockers have been used to treat SCI bladder dysfunction. These drugs target alpha adrenoreceptor blocker subtypes which may be implicated in a variety of mechanisms including bladder neck dysfunction, increased bladder outlet resistance, detrusor-sphincter dyssynergia, autonomic hyperreflexia or upper tract stasis.

Table 8 Summary of Alpha-Adrenergic Blockers

Author Year

Country
Research Design
Score
Total Sample Size

MethodsOutcome
Abrams et al. 2003

UK

 

Study 1: RCT

PEDro=8

Nintial=263; Nfinal=244

 

Study 2: Pre-Post

Nintial=186; Nfinal=134

Population: SCI: Mean age: 18 yr; Time since injury: 85-103 mo.

Intervention: Subjects were randomized to one of three groups; the 0.4mg tamsulosin, the 0.8mg tamsulosin or the placebo group. Medication or placebo were given once daily (after breakfast). Assessment for the groups was 2 and 4 weeks after treatment.

Outcome Measures: Urethral closure pressure.

1.     No significant change-maximal urethral closure pressure.

2.     Significant individual micturition diary change – 1) incontinence episode frequency and pad change freq reduced with tamsulosin: 0.04mg (p=0.009); 2) increase in mean void volume was seen in the 0.08mg group (p=0.003); however not in the 0.04 group.

Costa et al. 1993

France

RCT

PEDro=8

N=20

Population: SCI: Age range 18-60 yr; Gender: males=20, females=0; Time post-injury=4mo-7 yr.

Intervention: Moxisylyte at 0.25 mg, 0.50 mg, and 0.75 mg or placebo on different days separated by 4 to 7 days. According to the balance incomplete block design (3 treatments/individual).

Outcome Measures: Maximum urethral closure pressure (trapezoidal rule used on tracings); pre/post arterial blood pressure and heart rate; pharmacodynamic analysis.

1.     Treatment effects at 10min (p=0.0106).

2.     Decrease in diastolic blood pressure of 17.8%, 14%, and 5.2% after 0.75 mg, 0.50 mg, and 0.25 mg, respectively.

3.     Significant heart rate increases at 5, 10*, 15, 20, 30, 60 min (p=0.0016; *max).

4.     For 0.50 and 0.75 mg/kg, significant difference at 20min (p<0.02) but not at 15min (p=0.0598).

5.     Urethral closure pressure dose related-max of 47.6% reduction at 10min after 0.75 mg/kg.

Al-Ali et al. 1999

Iraq

Pre-Post

Ninitial=46; Nfinal=41

 

Population: SCI: Age range 13-49 yr.

Intervention: Phenoxybenzamine 10mg daily increased to 10 mg/twice daily and then 10 mg/3x daily for 3 wks to 6 mos.

Outcome measures: Urethral closure pressure.

1.     No statistically significant results reported.

2.     Improved max urethral closure pressure in 19 participants with reflex bladders.

3.     Non-responders=22 (9=areflexive bladders; 13=reflex bladders).

Perkash 1995

USA

Pre-Post

N=28

Population: SCI: Age range 20-74 yr; Severity of injury: Frankel: A, C-D.

Intervention: Terazosin for voiding.

Outcome Measures: Subjective assessment and detrusor voiding pressure (urodynamics).

1.     Subjective assessment –14 participants improved voiding, 14 participants no difference.

2.     Occasional autonomic dysreflexia in 11 participants.

3.     Decreased voiding pressure in 12 participants, no change in 10, and increased pressure in 6.

Linsenmeyer et al. 2002 USA

Case Series

N1=10; N2=7

Population: Study 1: Mean age: 28 yr; Gender: males=10, females=0; Severity of injury: AIS: A, B; Study 2: Gender: males=7, females=0.

Intervention: Study 1: impact of alpha blockers on upper tract stasis. Study 2: the impact of alpha blockers on urodynamic parameters in those with and without resolution of stasis.

Outcome Measures: Urodynamic parameters: mean changes in opening pressure, maximum detrusor voiding pressure and duration uninhibited contraction.

1.     Pre-treatment: 6 subjects taking prazosin, 4 taking terazosin.

2.     Three month treatment with alpha blockers resolves upper tract stasis (p<0.0003).

3.     Study 2: Uninhibited bladder contraction duration decreased with alpha-blocker usage (p<0.001).

4.     Mean arterial pressure during uninhibited contraction significantly decreased during alpha-blocker treatment (p<0.01).

Chancellor et al. 1993a USA
Case SeriesN1=15; N2=9
Population: SCI: Age range18-45 yr; Gender: males=15, females=0.

Intervention: Once Detrusor External Sphincter Dysynergia (DESD) without obstruction of the bladder neck or prostate was documented, therapy with terazosin (5mg daily) was initiated.

Outcome Measures: Voiding pressure.

1.     No significant differences in DESD voiding pressure after 4-12 weeks initial terazosin treatment (p=.48)

2.     Voiding pressure was reduced (p<0.001) after subsequent external sphincterotomy or sphincter stent placement.

3.     Out of 9 subjects who experienced persistent voiding symptoms after sphincterotomy following initial terazosin treatment, subsequent terazosin treatment improved voiding in participants with only bladder neck obstruction while the other 4 who did not improve had obstruction only at the external sphincter.

Note: SCI=Spinal Cord Injury, AIS=ASIA Impairment Scale

 

Discussion

Relieving symptoms of neurogenic bladder dysfunction by decreasing outflow resistance is achieved with alpha-1 blockers. Protection against the complications of chronic urinary retention is the primary intent of the therapeutic use of alpha-adrenergic blocking drugs for neurogenic bladder dysfunction.

Tamsulosin is an alpha-1 adrenoreceptor antagonist that has been used to treat SCI bladder neck dysfunction by relaxing smooth muscles in the bladder neck to improve urine flow rate. A large scale (n=263) study conducted by Abrams et al. (2003) provided evidence for decreased micturition frequency and improvement in urinary leakage parameters for individuals with SCI. The study was a 4-week RCT followed by an open-label period conducted over one year in persons with overactive bladder with or without dyssynergia. Maximal urethral pressure determined via urethral pressure profilometry demonstrated a significant reduction during the longer open-label period (p<0.001), but not the one-month RCT. In the 1-year open-label investigation, tamsulosin was also associated with improvement in several cystometry parameters related to bladder storage and emptying, as well as increased mean voided volume values as reported in a individual diary. Given that positive outcomes were more apparent during the open-label phase, which consisted of a pre-post trial design, the study has been assigned as level 4 evidence.

Moxisylyte is an alpha adrenoreceptor blocker used commonly in the treatment of Raynaud’s disease in which constriction of the blood vessels in the hands causes numbness and pain in the fingers. In a small RCT, Costa et al. (1993) investigated the off-label use of moxisylyte in the treatment of SCI bladder neck dysfunction due its property as a smooth muscle relaxant. A decrease in urethral closure pressure was found to be dose related and significant when compared to placebo, with the maximum reduction of 47.6% occurring 10 minutes following the administration of 0.75mg/kg in individuals with SCI.

Terazosin is most often used to treat hypertension. However, this alpha-adrenergic blocker can also used to treating bladder neck dysfunction by relaxing the bladder neck and reducing resistance to outflow during the voiding process. Perkash et al. (1995) reported that although 82% of individuals (N=28) without detrusor sphincter dyssynergia perceived improvement in voiding, only 42% registered objective decreases in maximum urodynamic voiding pressure. Side effects and tolerance may be deterrents to the wide-spread adoption of terazosin as an treatment for bladder neck dysfunction following SCI. The specificity of terazosin’s action on the bladder neck, exclusive of the external sphincter, was demonstrated by Chancellor et al. (1993a).

Phenoxybenzamine is an antihypertensive which is usually used to treat autonomic symptoms of pheochromocytomas such as high blood pressure or excess sweating. Al-Ali et al. (1999) undertook to utilize the autonomic effects of phenoxybenzamine to treat bladder dysfunction which is in part under autonomic control. Treatment with phenoxybenzamine resulted in a reduction of bladder outlet resistance, detrusor-sphincter dyssynergia and autonomic hyperreflexia in some subjects while no benefits were recorded for individuals with areflexive bladders. Phenoxybenzamine might therefore be beneficial as an adjunct treatment for neurogenic bladder dysfunction following SCI, when tapping or crede is unable to achieve satisfactory residual urine volumes of <100 mL. The lack of efficacy in those with bladder neck dysfunction was specifically noted in this study. Since statistically significant results were not reported in this study, further appropriately-sized RCTs are needed to establish the efficacy of phenoxybenzamine for treating neurogenic bladder dysfunction following SCI.

The pyelouretheral smooth muscle responsible for urethral peristalsis and movement of the urine from the kidneys to the bladder via the ureters is also a potential site of action for alpha 1-receptor antagonist therapy. In a small (n=10) retrospective chart review, Linsenmeyer et al. (2002) identified men with upper tract (i.e. kidneys and ureters) stasis secondary to SCI ≥T6 who used reflexive voiding to manage their bladders. After 6 months of alpha-1 blocker therapy, improvement in upper tract stasis was reported for 80% of the sample, as measured by significant decreases in duration of uninhibited bladder contractions. Firm conclusions about effectiveness and the optimum duration of treatment can only be validated with further RCTs.

Conclusion

There is level 1b evidence (from one RCT; Costa et al. 1993) that moxisylyte decreases maximum urethral closure pressure by 47.6% at 10 minutes after an optimum dose of 0.75 mg/kg in individuals with SCI.

There is level 4 evidence (from one pre-post study; Abrams et al. 2003) that tamsulosin may improve bladder neck relaxation and subsequent urine flow in individuals with SCI.

There is level 4 evidence (from one pre-post and one case series study; Perkash 1995; Chancellor et al. 1993a) that supports terazosin as an alternative treatment for bladder neck dysfunction in individuals with SCI; provided that side effects and drug tolerance are monitored.

There is level 4 evidence (from one case series study; Al-Ali et al. 1999) that suggests that phenoxybenzamine might have a role as an adjunct treatment for neurogenic bladder dysfunction following SCI, when tapping or crede is insufficient to achieve residual urine volumes <100mL.

There is level 4 evidence (from one case series study; Linsenmeyer et al. 2002) that 6 months of alpha-1 blocker therapy may improve upper tract stasis in men with SCI by decreasing the duration of involuntary bladder contractions.

Tamsulosin may improve urine flow in SCI individuals with bladder neck dysfunction.

Mosixylyte is likely able to decrease maximum urethral closure pressure at
a dose of 0.75mg/kg in individuals with SCI.

Terazosin may be an alternative treatment for bladder neck dysfunction in individuals with SCI; however, side effects and drug tolerance should be monitored.

Phenoxybenzamine may be useful as an adjunct therapy for reducing residual
urine volumes in individuals with SCI who manage their neurogenic bladder dysfunction by performing crede or tapping maneuvers.

Six months of alpha 1-blocker therapy in men with SCI may improve upper tract stasis.