Do the Effects of Oxybutynin on Cognition Depend on the Route of Administration_Topical or Oral? Results of a Double-Blind Placebo-Controlled Study in Healthy, Older Adults
Gary G. Kay, PhD1, David R. Staskin, MD2, Scott MacDiarmid, MD3, Marilyn McIlwain, MS4, Naomi V. Dahl, PharmD4.
1Cognitive Research Corporation, St. Petersburg, FL, USA, 2Tufts University Medical Center, Boston, MA, USA, 3Alliance Urology Specialists, Greensboro, NC, USA, 4Watson Laboratories, Inc., Morristown, NJ, USA.
Background: Oxybutynin is a common antimuscarinic agent for the treatment of overactive bladder (OAB). Previous studies have shown that oral oxybutynin formulations may impair cognitive functions in older adults, most likely as the result of action on the central muscarinic receptors. Oxybutynin chloride topical gel (OTG) 10% is a new transdermal formulation of oxybutynin chloride that is efficacious in improving OAB-related urinary symptoms with low incidences of peripheral anticholinergic adverse effects. To assess whether topically administered oxybutynin has a more favorable central nervous system profile than orally administered oxybutynin, a double-blind, placebo-controlled phase 1 study compared the effects of OTG and of oral oxybutynin immediate-release (OXB-IR) vs placebo on older adults’ cognitive and psychomotor functions.
Methods: Healthy adults aged 60 to 79 years were randomly assigned (1:1:1) to receive OTG (with oral placebo), OXB-IR (with gel placebo), or placebo (gel plus oral) for 1 week. Participants applied 1 gram of gel once daily to rotating sites on the abdomen, upper arms/shoulders, or thighs, and in addition took 1 capsule 3 times a day. Cognitive and psychomotor tests were conducted at baseline and study end. The primary end point was Name-Face Association Test (NFAT) delayed recall. Treatment groups were compared by ANCOVA.
Results: Of 152 participants, 49 received OTG, 52 OXB-IR, and 51 placebo. No significant treatment effect in NFAT delayed recall was observed overall (P=.2733) or between active treatments and placebo (OTG vs PBO, P=.1551; OXB-IR vs placebo, P=.1767). In contrast, a significant treatment effect (P=.0294) was observed for another measure of recent memory, the Misplaced Objects Test, with scores improving for placebo and OTG and declining for OXB-IR (OTG vs placebo, P=.3678; OXB-IR vs placebo, P=.0692). No significant group differences were observed for other tests of delayed recall (First-Last Name Association Test, Hopkins Verbal Learning Test [HVLT]-Delayed Recall, Retention, or Delayed Recognition Index) or for tests of immediate recall/working memory (NFAT, Facial Recognition Test, HVLT-Total Free Recall). However, Reliable Change scores for the HVLT-Revised test (e.g., a decline ≥6 from baseline on the Total Recall score) showed a significant decline from baseline to study end for 10 participants receiving OXB-IR, compared with 6 participants on placebo and 5 on OTG. No significant treatment effect was observed for psychomotor reaction time or Memory Assessment Clinics Self-Report Questionnaire variables. Most participants who reported adverse events were receiving OXB-IR. Dry mouth, the most common adverse event, occurred in 38 adults (73.1%) on OXB-IR, 3 (6.1%) on OTG, and 4 (7.8%) on placebo.
Conclusions: OTG had no significant effects on sensitive tests of memory and other cognitive functions in older adults. OTG was well tolerated with an incidence of anticholinergic events similar to that for placebo. Our findings suggest an additional safety and tolerability advantage of OTG over oral delivery of oxybutynin in older adults.
Research funded by Watson Pharma, Inc.
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