Detrol (Tolterodine) Side Effects Include Sleep Disturbance in Some Patients

Detrol (tolterodine) is a common medication for overactive bladder, a condition that causes a sudden, strong need to urinate, frequent trips to the bathroom and sometimes leaking. For most people it works well. But some people break down tolterodine much more slowly than others because of a gene called CYP2D6. In these people, more of the drug can reach the brain, and in one study it reduced their dream (REM) sleep. The good news is that there are other bladder medications that are less affected by this gene.

What is overactive bladder and how is it treated?

Overactive bladder happens when the bladder muscle squeezes too often or at the wrong time. Treatment usually starts without medication: cutting back on caffeine and alcohol, going to the bathroom on a schedule and doing pelvic floor exercises. If these are not enough, there are two main types of medications:

• Anticholinergic bladder medications, which calm the bladder muscle. Examples include tolterodine (Detrol), fesoterodine (Toviaz), oxybutynin, solifenacin (Vesicare), darifenacin and trospium.
• Beta-3 medications, mirabegron (Myrbetriq) and vibegron, which relax the bladder in a different way and do not have anticholinergic side effects.

How do your genes affect Detrol?

Your liver uses an enzyme called CYP2D6 to change tolterodine into a form that works just as well on the bladder but has a harder time getting into the brain. Your genes decide how well this enzyme works:

• Normal and ultrarapid metabolizers convert most of the tolterodine, so less of it reaches the brain.
• Intermediate and poor metabolizers convert less, so more tolterodine stays in the blood and can reach the brain and cause sleep disturbances.

About 1 in 15 people of European background are poor metabolizers, and many more are intermediate metabolizers. Because of these differences, the amount of active drug in the blood can vary a lot from person to person on the same dose of tolterodine.

Can Detrol affect your sleep?

It can in some people. In a sleep study, healthy volunteers took one dose of tolterodine at bedtime. People with reduced CYP2D6 activity had less REM sleep, the stage of sleep when we dream, which helps with memory and mood. People with normal CYP2D6 activity had no change. The volunteers did not notice a difference in how well they slept, and their thinking was not affected after one dose.

Drowsiness, confusion and other effects on the brain are not common with tolterodine, but they are more likely in people with reduced CYP2D6 activity, in older adults and in people who take other medications that cause drowsiness or have anticholinergic effects.

Which bladder medications are better for CYP2D6 poor metabolizers?

If you are a CYP2D6 poor or intermediate metabolizer, your prescriber may consider a medication that does not depend mainly on CYP2D6:

• Mirabegron (Myrbetriq) or vibegron. These beta-3 medications are not anticholinergic and are not greatly affected by CYP2D6. They are often a good choice for older adults. Note that mirabegron slows CYP2D6 itself, so it can raise the levels of other medications that depend on this enzyme, such as metoprolol and some antidepressants.
• Trospium. This anticholinergic is removed by the kidneys rather than the liver, and it enters the brain less than most others. It may need a lower dose in people with reduced kidney function.
• Solifenacin (Vesicare). It is broken down mainly by another liver enzyme, CYP3A4.

Darifenacin, like tolterodine, depends partly on CYP2D6, so it is less suitable for poor metabolizers.

Are bladder medications safe for older adults?

Overactive bladder is most common in older adults, who are also most sensitive to anticholinergic side effects such as dry mouth, constipation, blurry vision, confusion and falls. A large study of more than 280,000 people aged 55 and older found that taking anticholinergic bladder medications for several years was linked to a 65% higher risk of dementia. The American Geriatrics Society advises older adults to avoid strongly anticholinergic medications, such as oxybutynin, when possible.

If you are an older adult, ask your prescriber about non-drug treatments, beta-3 medications, or the lowest dose that works. Read more in Drug metabolism and aging.

How can a pharmacogenetic test help?

A Pillcheck test shows whether you are a poor, intermediate, normal or ultrarapid CYP2D6 metabolizer, and also reports CYP3A4 and other genes that affect bladder medications and many other drugs. Pillcheck reports on 24 genes, increasing coverage with new guidelines and drug labels (see the genes tab), and covers 355 medications, which account for over 70% of dispensed prescriptions. A Pillcheck pharmacist reviews your results and all your medications, checks how many have anticholinergic effects, and recommends safer options and doses to discuss with your prescriber.

Summary

• Your CYP2D6 gene affects how much Detrol (tolterodine) can reach your brain and affect your sleep.
• People with reduced CYP2D6 activity had less dream (REM) sleep after taking tolterodine in a sleep study.
• For CYP2D6 poor metabolizers, mirabegron, vibegron, trospium or solifenacin may be better options.
• Older adults should be careful with anticholinergic bladder medications, which have been linked to a higher risk of dementia with long-term use.
• A pharmacogenetic test and a pharmacist's review can help you and your prescriber choose the right bladder medication.

Frequently asked questions

Can Detrol cause sleep problems?

It can reduce dream (REM) sleep in people whose CYP2D6 enzyme works slowly. Drowsiness and confusion are uncommon, but more likely in these people and in older adults.

What can I take instead of Detrol if I am a CYP2D6 poor metabolizer?

Your doctor should consider alternative options, including mirabegron, vibegron, trospium and solifenacin.

Are bladder medications linked to dementia?

Taking anticholinergic bladder medications for several years has been linked to a higher risk of dementia in older adults. Ask your prescriber about the lowest dose that works or about beta-3 medications, which are not anticholinergic.

What can I do besides taking medication?

Bladder training, pelvic floor exercises and cutting back on caffeine and alcohol can help. For some people, treatments such as bladder Botox injections or nerve stimulation are options.

References

Diefenbach K, Jaeger K, Wollny A, et al. Effect of tolterodine on sleep structure modulated by CYP2D6 genotype. Sleep Med. 2008;9(5):579-582.

Malhotra B, Darsey E, Crownover P, et al. Comparison of pharmacokinetic variability of fesoterodine vs. tolterodine extended release in cytochrome P450 2D6 extensive and poor metabolizers. Br J Clin Pharmacol. 2011;72(2):226-234.

Coupland CAC, Hill T, Dening T, et al. Anticholinergic Drug Exposure and the Risk of Dementia: A Nested Case-Control Study. JAMA Intern Med. 2019;179(8):1084-1093.

2023 American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2023 updated AGS Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2023;71(7):2052-2081.