What's Hot in PD? Short and Long-Term Problems with Anticholinergic Drugs used for Sleep, Bladder, and Tremor Symptoms in Parkinson’s Disease Patients

People with Parkinson's disease (PD) frequently struggle to identify drug therapies that can address bothersome symptoms such as sleep dysfunction, bladder urgency, drooling and tremor. Many of the drug therapies such as Benadryl (diphenhydramine), Advil PM, Alleve PM, common antihistamines, and others pills are readily available over the counter and do not require a prescription. These medications block a cholinergic receptor in the brain, and can improve many Parkinson’s disease symptoms. However, the price of taking these drugs may be steep (thinking problems, confusion, unsteadiness and even falling). An older French study of hospitalized Parkinson’s disease patients revealed that though 46% of all demented patients were confused, 93% on anticholinergic therapy had delirium and confusion when in the hospital (Agid et. al.). Deficiencies of the chemical acetylcholine have been reported to underpin thinking issues and shortages of the chemical have been observed in the brainstem, hippocampus, and cortex of Parkinson’s disease patients. Though anticholinergic use can result in drowsiness, dry mouth, urinary retention, memory problems as well as constipation, many patients find these therapies useful. In this month’s What’s Hot column we will address the short and long-term potential side effects of using of anticholinergic medications in Parkinson’s disease.

Cooper and colleagues in 1992 addressed thinking ability in a group of 82 freshly diagnosed and untreated Parkinson’s disease patients. The patients in this study were all randomized to receive levodopa (Sinemet), bromocriptine (a dopamine agonist) or an anticholinergic drug. Though all three treatments improved motor performance, the anticholinergic drugs produced memory impairments. Many subsequent studies including the Parkinson's Foundation QII prospective study have confirmed these findings.

Perry and colleagues in 2003 investigated the idea that blocking brain acetylcholine receptors could lead to more “Alzheimer’s changes” in the Parkinson’s disease brain. Interestingly, the researchers reported that an important marker of Alzheimer's disease, the amyloid plaque density, was present in more than double the concentration in Parkinson’s disease patients treated with long-term anticholinergic therapy. Another marker of Alzheimer’s disease, the neurofibrillary tangle, was also more prominent in the brains of those taking anticholinergic drugs.

The most recent worrisome evidence surrounding anticholinergic therapy is drawn from an article in a recent issue of JAMA Internal Medicine written by pharmacist Shelly Gray. The authors utilized data from the Adult Changes in Thought Study. The investigation was based in Washington state and had an impressive 3,434 people enrolled who were 65 years or older. All study participants were screened at inclusion to be sure there was no evidence for dementia. The authors cleverly used computerized pharmacy data to assess each participant’s exposure to anticholinergic drugs. The most common anticholinergic drugs were old-fashioned tricyclic antidepressants (TCA’s), antihistamines, and also drugs used for bladder and sleep. The patients were followed for 7 years and the data revealed that over 20% were shown to develop dementia. Participants who took anticholinergic drugs for three years or more had a greater than 50% higher dementia risk. Also, a higher cumulative dose of anticholinergic drugs increased the risk for dementia when compared to those taking anticholinergic drugs for 90 days or less.

The bottom line for people with Parkinson’s is that there should be a greater awareness of the short and the long-term potential side effects of anticholinergic therapy. Short-term, Parkinson’s patients should be aware that anticholinergics may precipitate drowsiness, dry mouth, urinary retention, memory problems, blurry vision, and constipation as well as a host of other side effects. Long-term, there is an increased risk of dementia. It is important for people with PD to routinely review medication lists with both a doctor and a pharmacist and to try to identify other medication alternatives.

Some practical suggestions include:

• Identify alternative antidepressants with less anticholinergic effects
• Watch out for over the counter drugs like Benadryl (diphenhydramine) and antihistamines
• Dopamine agonists, levodopa, and deep brain stimulation can all potentially be used for difficult to control tremor instead of anticholinergics
• Botulinum toxin injections can be employed for drooling and for some cases of bladder dysfunction
• Sometimes atropine drops under the tongue or chewing gum can be employed for drooling issues
• A type of physical therapy referred to as pelvic floor rehabilitation can be helpful for bladder retraining in those with urinary frequency
• If hospitalized be sure the doctors do not use anticholinergics for sleep or bladder dysfunction
• Parkinson’s disease patients and their interdisciplinary care teams can usually work together to reduce or to eliminate anticholinergic drug use

Selected References:

Cooper JA, Sagar HJ, Doherty SM, Jordan N, Tidswell P, Sullivan EV. Different effects of dopaminergic and anticholinergic therapies on cognitive and motor function in Parkinson's disease. A follow-up study of untreated patients. Brain. 1992 Dec;115 ( Pt 6):1701-25. PubMed PMID: 1486457.

Perry EK, Kilford L, Lees AJ, Burn DJ, Perry RH. Increased Alzheimer pathology in Parkinson's disease related to antimuscarinic drugs. Ann Neurol. 2003 Aug;54(2):235-8. PubMed PMID: 12891676.

Bédard MA, Pillon B, Dubois B, Duchesne N, Masson H, Agid Y. Acute and long-term administration of anticholinergics in Parkinson's disease: specific effects on the subcortico-frontal syndrome. Brain Cogn. 1999 Jul;40(2):289-313. PubMed PMID: 10413563.

Gray SL, Anderson ML, Dublin S, Hanlon JT, Hubbard R, Walker R, Yu O, Crane PK, Larson EB. Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern Med. 2015 Mar;175(3):401-7. doi: 10.1001/jamainternmed.2014.7663. PubMed PMID: 25621434; PubMed Central PMCID: PMC4358759.

Faulkner MA. Safety overview of FDA-approved medications for the treatment of the motor symptoms of Parkinson's disease. Expert Opin Drug Saf. 2014 Aug;13(8):1055-69. doi: 10.1517/14740338.2014.931369. Epub 2014 Jun 24. Review. PubMed PMID: 24962891.

Sakakibara R. [Cognitive adverse effects of anticholinergic medication for overactive bladder in PD/DLB]. Rinsho Shinkeigaku. 2013;53(11):1389-92. Review. Japanese. PubMed PMID: 24292000.

Campbell NL, Boustani MA. Adverse cognitive effects of medications: turning attention to reversibility. JAMA Intern Med. 2015 Mar;175(3):408-9. doi: 10.1001/jamainternmed.2014.7667. PubMed PMID: 25622111; PubMed Central PMCID: PMC4346513.

Mate KE, Kerr KP, Pond D, Williams EJ, Marley J, Disler P, Brodaty H, Magin PJ. Impact of multiple low-level anticholinergic medications on anticholinergic load of community-dwelling elderly with and without dementia. Drugs Aging. 2015 Feb;32(2):159-67. doi: 10.1007/s40266-014-0230-0. PubMed PMID: 25566958.

Kalisch Ellett LM, Pratt NL, Ramsay EN, Barratt JD, Roughead EE. Multiple anticholinergic medication use and risk of hospital admission for confusion or dementia. J Am Geriatr Soc. 2014 Oct;62(10):1916-22. doi: 10.1111/jgs.13054. Epub 2014 Oct 3. PubMed PMID: 25284144.

Kidd AC, Musonda P, Soiza RL, Butchart C, Lunt CJ, Pai Y, Hameed Y, Fox C, Potter JF, Myint PK. The relationship between total anticholinergic burden (ACB) and early in-patient hospital mortality and length of stay in the oldest old aged 90 years and over admitted with an acute illness. Arch Gerontol Geriatr. 2014

Jul-Aug;59(1):155-61. doi: 10.1016/j.archger.2014.01.006. Epub 2014 Feb 5. PubMed PMID: 24582945.

Dubois B, Pilon B, Lhermitte F, Agid Y. Cholinergic deficiency and frontal dysfunction in Parkinson's disease. Ann Neurol. 1990 Aug;28(2):117-21. PubMed PMID: 2221841.

Dubois B, Danzé F, Pillon B, Cusimano G, Lhermitte F, Agid Y. Cholinergic-dependent cognitive deficits in Parkinson's disease. Ann Neurol. 1987 Jul;22(1):26-30. PubMed PMID: 3631918.

Dubois B, Ruberg M, Javoy-Agid F, Ploska A, Agid Y. A subcortico-cortical cholinergic system is affected in Parkinson's disease. Brain Res. 1983 Dec 12;288(1-2):213-8. PubMed PMID: 6661617.

You can find out more about our National Medical Director, Dr. Michael S. Okun, by also visiting the Center of Excellence, University of Florida Health Center for Movement Disorders and Neurorestoration. Dr. Okun is also the author of the Amazon #1 Parkinson's Best Seller 10 Secrets to a Happier Life and 10 Breakthrough Therapies for Parkinson's Disease.