Oxybutynin-Associated Cognitive Impairment: Evidence and Implications for Overactive Bladder Treatment - Beyond the Abstract
July 10, 2024
Anticholinergic medications have long been mainstays of overactive bladder (OAB) treatment. Oxybutynin, a first-generation anticholinergic, still accounts for more than half of all OAB medication prescriptions, despite associations with impaired memory and cognition, as well as mounting evidence that it may increase the risk of incident dementia.
Biographies:
Michael Chancellor, MD, Corewell Health Beaumont University Hospital, Oakland University William Beaumont School of Medicine, Royal Oak, MI
Biographies:
Michael Chancellor, MD, Corewell Health Beaumont University Hospital, Oakland University William Beaumont School of Medicine, Royal Oak, MI
Read the Full Video Transcript
Michael Chancellor: Hi, I'm Dr Michael Chancellor. I'm a Urologist at Corewell Health, Beaumont University Hospital, and a Professor at the Oakland University William Beaumont School of Medicine. The AUA treatment guidelines for overactive bladder recommend behavior therapy and also pharmacotherapies, either oral anticholinergic or β 3-adrenergic receptor agonists may be combined with behavior therapy.
Anticholinergics, including oxybutynin, represent more than 80% of Medicare claims for overactive bladder medication in 2017. This may be driven by its low cost, along with insurance requirements for patients to try an anticholinergic before other treatments are approved. Although anticholinergics have demonstrated efficacy and reducing OAB symptoms, a growing body of evidence has found association between anticholinergic use/overburden and the increased risk of more serious adverse outcomes, such as cognitive impairment and dementia, and this is especially so in the elderly patients. There are 5 muscarinic receptors, M1 through 5, which are expressed in the various organs in our body, with M3 receptors being the predominant expressed in the bladder. So, in addition to blocking the activation of the M3 receptors in the detrusor muscle, oxybutynin can potentially inhibit the remaining other 4 types of muscarinic receptors at its physiologic concentration. So, this raises the possibility of really broad off target effects.
And because oxybutynin is lipophilic, it is neutrally charged, small molecular weight, it can diffuse across the blood brain barrier with ease, and this could potentially affect the muscarinic receptors in the brain that are involved in the cognitive/cognition process. So furthermore, oxybutynin is really not effectively cleared from the brain by the efflux transporter, such as the P-glycoprotein. So preclinical and clinical evidence support the association between oxybutynin and impairment of memory and attention. The first study that systematically evaluated the cognitive impact of oxybutynin was using the immediate release in human, and this was published by Katz and associates in 1998. The study found an association between oxybutynin treatment and significant memory impairment, and this was assessed through tests measuring total recall, long-term storage, long-term recall, and incidental memory pattern memory. So, oxybutynin treatment also impairs concentration and reaction time. In 150 healthy participants over the age of 60 who received the extended-release formulation of oxybutynin found that the degree of memory change after 3 weeks of oxybutynin treatment was comparable to the decline that occur over 10 years of normal aging.
Several observational studies, commonly retrospective analysis, also found that the treatment with anticholinergic and this include oxybutynin, is associated with cognitive impairment, delirium, and increased dementia risk. Professional medical organizations have recently responded to the growing evidence of risk associated with anticholinergics by recommending that clinicians carefully consider, and ultimately limit, the use of anticholinergic to treat overactive bladder. A SUFU white paper suggests that sharing clinician patient decision making is a good idea to weigh the potential benefit of anticholinergics against the potential risk of dementia. SUFU caution cautions that the chronic use of overactive bladder anticholinergics of more than 3 months of use is likely to be associated with increased risk of new-onset dementia. However, short-term use, that of less than 4 weeks, of most anticholinergic is likely to be safe in most individuals. American Urogynecologic Society recommend minimizing anticholinergic burden by using nonanticholinergic therapies when appropriate for older adults and those with cognitive impairment. And finally, the American Geriatrics Society recommend avoiding or minimizing the number of anticholinergic drugs, including those that treat overactive bladder.
In summary, there's an overwhelming amount of preclinical, clinical, and real-world evidence linking the use of oxybutynin and other anticholinergics to adverse cognitive outcome, including impaired memory and increased dementia risk. Currently, available data on OAB prescribing patterns suggests that oxybutynin use remains high. It’s likely due to its low cost and [insurance company] step-therapy requirements. However, clinicians should carefully consider the cognitive risk of their patients with overactive bladder and consider reviewing treatment options and patients currently receiving oxybutynin.
Michael Chancellor: Hi, I'm Dr Michael Chancellor. I'm a Urologist at Corewell Health, Beaumont University Hospital, and a Professor at the Oakland University William Beaumont School of Medicine. The AUA treatment guidelines for overactive bladder recommend behavior therapy and also pharmacotherapies, either oral anticholinergic or β 3-adrenergic receptor agonists may be combined with behavior therapy.
Anticholinergics, including oxybutynin, represent more than 80% of Medicare claims for overactive bladder medication in 2017. This may be driven by its low cost, along with insurance requirements for patients to try an anticholinergic before other treatments are approved. Although anticholinergics have demonstrated efficacy and reducing OAB symptoms, a growing body of evidence has found association between anticholinergic use/overburden and the increased risk of more serious adverse outcomes, such as cognitive impairment and dementia, and this is especially so in the elderly patients. There are 5 muscarinic receptors, M1 through 5, which are expressed in the various organs in our body, with M3 receptors being the predominant expressed in the bladder. So, in addition to blocking the activation of the M3 receptors in the detrusor muscle, oxybutynin can potentially inhibit the remaining other 4 types of muscarinic receptors at its physiologic concentration. So, this raises the possibility of really broad off target effects.
And because oxybutynin is lipophilic, it is neutrally charged, small molecular weight, it can diffuse across the blood brain barrier with ease, and this could potentially affect the muscarinic receptors in the brain that are involved in the cognitive/cognition process. So furthermore, oxybutynin is really not effectively cleared from the brain by the efflux transporter, such as the P-glycoprotein. So preclinical and clinical evidence support the association between oxybutynin and impairment of memory and attention. The first study that systematically evaluated the cognitive impact of oxybutynin was using the immediate release in human, and this was published by Katz and associates in 1998. The study found an association between oxybutynin treatment and significant memory impairment, and this was assessed through tests measuring total recall, long-term storage, long-term recall, and incidental memory pattern memory. So, oxybutynin treatment also impairs concentration and reaction time. In 150 healthy participants over the age of 60 who received the extended-release formulation of oxybutynin found that the degree of memory change after 3 weeks of oxybutynin treatment was comparable to the decline that occur over 10 years of normal aging.
Several observational studies, commonly retrospective analysis, also found that the treatment with anticholinergic and this include oxybutynin, is associated with cognitive impairment, delirium, and increased dementia risk. Professional medical organizations have recently responded to the growing evidence of risk associated with anticholinergics by recommending that clinicians carefully consider, and ultimately limit, the use of anticholinergic to treat overactive bladder. A SUFU white paper suggests that sharing clinician patient decision making is a good idea to weigh the potential benefit of anticholinergics against the potential risk of dementia. SUFU caution cautions that the chronic use of overactive bladder anticholinergics of more than 3 months of use is likely to be associated with increased risk of new-onset dementia. However, short-term use, that of less than 4 weeks, of most anticholinergic is likely to be safe in most individuals. American Urogynecologic Society recommend minimizing anticholinergic burden by using nonanticholinergic therapies when appropriate for older adults and those with cognitive impairment. And finally, the American Geriatrics Society recommend avoiding or minimizing the number of anticholinergic drugs, including those that treat overactive bladder.
In summary, there's an overwhelming amount of preclinical, clinical, and real-world evidence linking the use of oxybutynin and other anticholinergics to adverse cognitive outcome, including impaired memory and increased dementia risk. Currently, available data on OAB prescribing patterns suggests that oxybutynin use remains high. It’s likely due to its low cost and [insurance company] step-therapy requirements. However, clinicians should carefully consider the cognitive risk of their patients with overactive bladder and consider reviewing treatment options and patients currently receiving oxybutynin.