Randomised, Double-Blind Study
Objective: Central nervous effects of oral anticholinergics may limit the success of incontinence therapy and patient compliance. Only a few studies investigating this topic are available. This study was conducted to determine whether oral anticholinergics alter sleep and psychometric test parameters.
Design: Randomised, double-blind, crossover, placebo-controlled study.
Study participants: 24 healthy volunteers (age 22-36 years) without sleeprelated problems.
Interventions: Polysomnographic recordings, sleep questionnaires and psycho-metric tests (the number combination test [Zahlen-Verbindungs Test; ZVT] and the d2 attention test) were performed following single doses of oxybutynin 15mg, tolterodine 4mg, trospium chloride 45mg or placebo, each separated by an 8-day washout period.
Results: Rapid eye movement (REM) sleep (relative to total sleep time) was the primary parameter of polysomnography. The REM sleep for oxybutynin was significantly lower than that for trospium chloride (18.4% vs 20.2%; p < 0.05) and lower than that for placebo (20.1%; ns). The number combination test (ZVT), the primary parameter of cognitive function, and the d2 test did not reveal any differences in reaction time. With regard to the other sleep parameters, the REM latency for oxybutynin was clearly higher than that for placebo, trospium chloride and tolterodine. Effects on non-REM sleep were observed only after administration of oxybutynin compared with placebo.
Conclusions: Oxybutynin influenced sleep structure, as was reflected by REM suppression and mild sedation, while subjective parameters and psychometric tests remained unaffected. The sleep and psychometric test values for tolterodine and trospium chloride were comparable to those of placebo. The clinical relevance of these effects is small in healthy young volunteers, but these results cannot be extended to the elderly.
Urinary incontinence is a common problem estimated to occur in 10-30% of all elderly women and in 2-3% of elderly men. Anticholinergic drugs such as trospium chloride, tolterodine and oxybutynin are widely used for treatment of detrusor hyperactivity and hyperreflexia of the urinary bladder. The success of therapy and patient compliance are often impaired by the typical adverse effects of these drugs, such as dry mouth, gastrointestinal disturbances and visual disorders. However, side effects in the central nervous system are more critical, especially in elderly individuals. Their incidence and intensity associated with different anticholinergic agents can vary: clinical studies revealed cognitive impairment and changes in central nervous electrical activity after treatment with oxybutynin, whereas trospium chloride did not cause any impairment. Neuropsychological adverse effects including psychosis, hallucination, confusion, cognitive impairment, impaired concentration and orientation, as well as drowsiness and disturbed sleep behaviour, have been observed in conjunction with oxybutynin. Tolterodine leads to central nervous adverse effects such as dizziness, sleepiness and nervousness, whereas no effects of this type have been observed with trospium chloride. The distinct pharmacodynamic and pharmacokinetic properties of the anticholinergic drugs seem to be responsible for these differences. The ability of a substance to cross the blood-brain barrier depends on its structure, i.e. on its lipophilicity, electrical charge and molecular size. Small, lipophilic, noncharged molecules and compounds containing a tertiary ammonium group pass the blood-brain barrier more readily than those containing a quaternary ammonium group or groups with opposing characteristics. Whereas oxybutynin and tolterodine are tertiary amines, trospium chloride is a quaternary ammonium compound.
Oxybutynin, tolterodine and trospium chloride do not appear to selectively block muscarinic receptor subtypes M1 to M5, although functional differences in the affinity to muscarinic receptors in different organs may be an explanation for the different qualities of their anticholinergic effects.
There is strong evidence that anticholinergic compounds influence sleep structure and sleep quality. Five case reports of pavor nocturnus (`night terror ) after administration of oxybutynin have been described. Neuropsychological adverse effects have been reported in conjunction with several anticholinergic drugs and other substances with anticholinergic properties. Distinct changes in sleep structure were observed after treatment with the nonselective cholinergic antagonist scopolamine. These changes along with an up to 130% increase in rapid eye movement (REM) latency and a 20-60% reduction in REM duration are more pronounced in REM sleep than in non-REM sleep. The aim of the present study was to compare the effects of oxybutynin, tolterodine and trospium chloride versus placebo on sleep parameters in healthy individuals. Subjective assessments of sleep and cognitive behaviour were analysed in addition to the usual polysomnographic parameters of sleep structure.
Objective: Central nervous effects of oral anticholinergics may limit the success of incontinence therapy and patient compliance. Only a few studies investigating this topic are available. This study was conducted to determine whether oral anticholinergics alter sleep and psychometric test parameters.
Design: Randomised, double-blind, crossover, placebo-controlled study.
Study participants: 24 healthy volunteers (age 22-36 years) without sleeprelated problems.
Interventions: Polysomnographic recordings, sleep questionnaires and psycho-metric tests (the number combination test [Zahlen-Verbindungs Test; ZVT] and the d2 attention test) were performed following single doses of oxybutynin 15mg, tolterodine 4mg, trospium chloride 45mg or placebo, each separated by an 8-day washout period.
Results: Rapid eye movement (REM) sleep (relative to total sleep time) was the primary parameter of polysomnography. The REM sleep for oxybutynin was significantly lower than that for trospium chloride (18.4% vs 20.2%; p < 0.05) and lower than that for placebo (20.1%; ns). The number combination test (ZVT), the primary parameter of cognitive function, and the d2 test did not reveal any differences in reaction time. With regard to the other sleep parameters, the REM latency for oxybutynin was clearly higher than that for placebo, trospium chloride and tolterodine. Effects on non-REM sleep were observed only after administration of oxybutynin compared with placebo.
Conclusions: Oxybutynin influenced sleep structure, as was reflected by REM suppression and mild sedation, while subjective parameters and psychometric tests remained unaffected. The sleep and psychometric test values for tolterodine and trospium chloride were comparable to those of placebo. The clinical relevance of these effects is small in healthy young volunteers, but these results cannot be extended to the elderly.
Urinary incontinence is a common problem estimated to occur in 10-30% of all elderly women and in 2-3% of elderly men. Anticholinergic drugs such as trospium chloride, tolterodine and oxybutynin are widely used for treatment of detrusor hyperactivity and hyperreflexia of the urinary bladder. The success of therapy and patient compliance are often impaired by the typical adverse effects of these drugs, such as dry mouth, gastrointestinal disturbances and visual disorders. However, side effects in the central nervous system are more critical, especially in elderly individuals. Their incidence and intensity associated with different anticholinergic agents can vary: clinical studies revealed cognitive impairment and changes in central nervous electrical activity after treatment with oxybutynin, whereas trospium chloride did not cause any impairment. Neuropsychological adverse effects including psychosis, hallucination, confusion, cognitive impairment, impaired concentration and orientation, as well as drowsiness and disturbed sleep behaviour, have been observed in conjunction with oxybutynin. Tolterodine leads to central nervous adverse effects such as dizziness, sleepiness and nervousness, whereas no effects of this type have been observed with trospium chloride. The distinct pharmacodynamic and pharmacokinetic properties of the anticholinergic drugs seem to be responsible for these differences. The ability of a substance to cross the blood-brain barrier depends on its structure, i.e. on its lipophilicity, electrical charge and molecular size. Small, lipophilic, noncharged molecules and compounds containing a tertiary ammonium group pass the blood-brain barrier more readily than those containing a quaternary ammonium group or groups with opposing characteristics. Whereas oxybutynin and tolterodine are tertiary amines, trospium chloride is a quaternary ammonium compound.
Oxybutynin, tolterodine and trospium chloride do not appear to selectively block muscarinic receptor subtypes M1 to M5, although functional differences in the affinity to muscarinic receptors in different organs may be an explanation for the different qualities of their anticholinergic effects.
There is strong evidence that anticholinergic compounds influence sleep structure and sleep quality. Five case reports of pavor nocturnus (`night terror ) after administration of oxybutynin have been described. Neuropsychological adverse effects have been reported in conjunction with several anticholinergic drugs and other substances with anticholinergic properties. Distinct changes in sleep structure were observed after treatment with the nonselective cholinergic antagonist scopolamine. These changes along with an up to 130% increase in rapid eye movement (REM) latency and a 20-60% reduction in REM duration are more pronounced in REM sleep than in non-REM sleep. The aim of the present study was to compare the effects of oxybutynin, tolterodine and trospium chloride versus placebo on sleep parameters in healthy individuals. Subjective assessments of sleep and cognitive behaviour were analysed in addition to the usual polysomnographic parameters of sleep structure.