Particularly for urge incontinence and associated symptoms falling under the heading of “overactive bladder,” new drugs are always being developed and existing drugs can be found to have a potentially new application. Drugs recently added to those FDA-approved for urge incontinence have relied primarily on their anticholinergic effects. In contrast, tramadol, a drug FDA-approved for pain relief (marketed in the United States as Ultram), was tested for this use. Although the mechanism of action is unknown, the authors proposed a possible change in dopamine receptor activation.
Treated group improved, placebo group did not
Safarinejad MR, Hosseini SY. Safety and efficacy of tramadol in the treatment of idiopathic detrusor overactivity: a double-blind, placebo-controlled, randomized study. Br J Clin Pharmacol. 2006;61:456–463.
This randomized, placebo-controlled trial included 76 men and women with detrusor overactivity. The study population was relatively young, with mean ages of 39 and 37 years in the drug and placebo groups, respectively, and included about 2/3 women. At a sustained-release dose of 100 mg twice a day for 12 weeks of study, tramadol was effective for reducing the number of urge incontinence episodes per 24 hours from a baseline mean of 3.2 ±3.3 episodes to a mean of 1.6 ± 2.8 episodes. In addition, frequency of voiding per 24 hours was reduced (baseline mean 9.3 ± 3.2 episodes, to 5.1 ± 2.1) and the mean volume per void increased substantially (158 ± 32 mL, to 198 ± 76 mL) without an increase in postvoid residual urine volume.
In contrast to the results of many placebo-controlled drug trials and even with the use of 24-hour voiding diaries every 2 weeks for the 12-week study, the placebo group showed essentially no change in clinical and urodynamic outcomes. For example, the number of urge incontinence episodes per 24 hours was unchanged, from a baseline mean of 3.3 ± 3.1 episodes, to a mean of 3.1 ± 3.0 after 12 weeks. Nausea was the most commonly reported side effect (18% vs 5% in the drug and placebo groups, respectively); 2 of 35 participants in the tramadol group dropped out of the study due to nausea.
Confirmation of these results and further study may shed light on the complex control of normal voiding and the true etiology behind the symptoms that we call “detrusor overactivity,” and potentially open a new class of drugs for treatment.
Delivery mode and genetic influences on urinary incontinence
Rohr G, Kragstrup J, Gaist D, Christensen K. Genetic and environmental influences on urinary incontinence: a Danish population-based twin study of middle-aged and elderly women. Acta Obstet Gynecol Scand. 2004;83:978–982.
Goldberg RP, Abramov Y, Botros S, et al. Delivery mode is a major environmental determinant of stress urinary incontinence: results of the Evanston–Northwestern Twin Sisters Study. Am J Obstet Gynecol. 2005;193:2149–2153.
The genetic predisposition for urinary incontinence, seen in clinical practice as clustering in families—mothers, daughters, sisters—has been long suspected, and has been supported in recent studies of nature’s gift to genetic research—twins. In a study of more than 1,000 Danish twins in 2 age groups, Rohr et al were able to quantitatively estimate the heritable component for urinary incontinence, which was categorized by questionnaire into urge, mixed, and stress incontinence. The study included 548 monozygotic twin pairs (who share identical genetic material) and 620 dizygotic twin pairs (who, on average, share 50% of their genes like ordinary sisters).
Urge incontinence, in both age groups, had a similar level of heritability: 42% for ages 46–68 and 49% for ages 70–94.
Mixed incontinence had a lower level of heritability: 27% in middle age and 55% in the older group.
Stress incontinence in the older group had a significant heritable component at 39%, but stress incontinence in the middle-aged group was more strongly associated with environmental factors than with heritability.
Another study focused on stress incontinence in a study of 271 monozygotic twin pairs with a mean age of 47 years. Within the 173 parous twin pairs, environmental factors associated with stress incontinence were identified: age, parity, obesity, and mode of delivery.
Childbirth and genetic factors. These data clarify an important area of (apparently) inconsistent epidemiologic literature on the role of childbirth, and particularly mode of delivery, in lifetime risk of urinary incontinence. The inconsistency resolves once age of the study cohort and type of incontinence are considered. Stress incontinence is influenced most strongly by mode of delivery in middle-aged women. Later in life, genetic factors play a more important role in risk of stress incontinence, and mode of delivery becomes less important. Urge incontinence, perhaps developing along a different etiologic path than stress incontinence, is strongly influenced by heritability in both middle-aged and older women; environmental factors influencing the development of urge incontinence are less important through the lifespan.