Focus on Parkinson’s disease – Part 1

Contributed by: Joyce Lee MD CCFP COE, BScPharm – View bio

Case

Amanda is a 72-year-old retired teacher with an eight-year history of Parkinson’s disease (PD). Her past medical history includes hypertension, anxiety and type 2 diabetes mellitus (DM). She lives with her husband Ben in a bungalow and uses a walker for ambulation. Her medications include: 

1. levodopa/carbidopa 100/25 1.5 tablets po five times daily
2. levodopa/carbidopa CR 100/25 po qhs (controlled release)
3. perindopril 8 mg po daily
4. amlodipine 5 mg po daily
5. metformin 500 mg po bid
6. sertraline 50 mg po qhs

She presents to you with recent falls. Ben reports she has had a weight loss of 10 pounds over six months with poor appetite. She yells and moves in her sleep almost nightly.

Issue

Identify any potential prescribing issues, including adverse effects, drug-disease interactions and/or prescribing omissions which may be relevant in this case.

Background

PD affects 1% of the population over age 60.¹ The vast majority (over 90%) of people affected by PD/parkinsonism are aged over 60,² making PD a very relevant issue in caring for older patients. Indeed, PD is the second most common neurodegenerative disease affecting the aged, and is growing more rapidly than Alzheimer’s disease.^1,3 

PD is characterized by the classic motor symptoms of bradykinesia, plus one or more of low frequency (4-6 Hz) resting tremor and rigidity, with postural changes usually as a later symptom. Non-motor symptoms of PD include autonomic features and neuropsychiatric/sleep issues.⁴

Autonomic symptoms include: 

• orthostatic hypotension
• constipation 
• urinary urge with frequency
• sexual dysfunction
• thermodysregulation and sweating

Neuropsychiatric/sleep issues include: 

• dementia – not typical in early PD, but increases to 80% prevalence by eight years⁵
• visual hallucinations – not typical in early PD, may be exacerbated by medications
• depression/anxiety – missed in routine neurology assessments more than half the time in PD⁶
• REM behaviour disorder (RBD) 
• restless legs syndrome
• excessive daytime sleepiness/fatigue

Table 1 below shows the prevalence of these non-motor symptoms:

Table 1: Non-motor features of Parkinson’s disease – prevalence¹

Assessment and evidence

Amanda presents with multiple symptoms that will be impacted by the practitioners’ choice of medications: REM sleep behaviour disorder, falls, weight loss, orthostatic hypotension and constipation. 

REM behaviour disorder

REM behavior disorder (RBD) is the lack of large muscle atonia during REM sleep, leading to enactment of dreams, and may predate motor symptoms in PD by decades.⁸ Asking patients and their bed partners specific questions about vivid dreams, yelling and moving in sleep, and hypnopompic hallucinations (hallucinations upon waking) is important. RBD can disrupt sleep quality and is exacerbated by antidepressants (TCAs, SNRIs, SSRIs, mirtazapine) with serotonergic/noradrenergic properties.^9–12 

From her presentation, Amanda has RBD. This disorder is often exacerbated by sertraline (an SSRI) and many commonly used antidepressants, especially when given at bedtime. SSRI’s or SNRI’s would generally be better choices than TCA’s for depression/anxiety in PD due to side effect profile. Using the minimum effective dose with administration early in the day may be helpful to minimize RBD, thus Amanda should take sertraline with breakfast or lunch. 

Melatonin and clonazepam are effective for RBD.¹⁰ Clonazepam has more adverse effects and should be reserved as second line. Melatonin dual action or extended release at 5 mg at bedtime is recommended for Amanda as most RBD events occur in the early morning during the latter part of the sleep period.

Falls, weight loss, orthostatic hypotension (OH), constipation

Contributing factors to falls in PD include OH, postural instability, freezing of gait and cognitive decline. Amanda has DM and PD, which increase her risk of autonomic dysfunction and OH. She may not tolerate the same doses of antihypertensives as before. 

Orthostatic vitals including BP and HR sitting, then standing (immediate and after two minutes) should be part of the routine examination of a PD patient. Lack of HR increase while BP drops with position change suggests autonomic dysfunction. BP meds should be reduced and given at bedtime to treat potential supine hypertension (common in PD autonomic dysfunction), and reduce impact on daytime BP. Other non-pharmacological measures including fluids, salt and abdominal binder can be reviewed in the literature.

Weight loss results in relative dopaminergic excess and exaggerated levodopa side effects, as levodopa dosing is weight-based.¹³ Weight measurement should be part of a routine visit with a patient with PD. Amanda lost 10 pounds due to poor appetite, which may be due to mood or constipation. Her levodopa dosing needs to be reduced gently (by 10 – 20%), especially if patient presents with symptoms of dopaminergic excess, such as psychosis, impulsivity, hallucinations and increased dyskinesias (involuntary movements) at peak dose (usually one – two hours after dose). 

Constipation is very common in PD and DM, and should always be screened for in routine visits as follows: 

1. How often do you have a bowel movement?
2. What does your BM look like (Bristol stool chart)?

Constipation can result in poor oral intake, dehydration, poor levodopa absorption and worsened motor symptoms, urinary retention and frequency/incontinence, and worse OH (from poor intake) leading to symptoms of hypotension and falls. General measures include increasing dietary fibre, fluids, exercise and discontinuing exacerbating medications (e.g., opioids, antipsychotics and anticholinergics). A bowel routine should be routinely prescribed with Polyethylene glycol 3350 (PEG) being most evidence-based.¹⁴ 

Stimulant laxatives (sennosides and bisacodyl) should be used in select patients, preferably on an as-needed basis.² Patients who have limited mobility and physical activity, who have known autonomic dysfunction (from PD, DM or other etiologies), or who are on medications which reduce gastrointestinal (GI) motility (i.e., anticholinergics, antipsychotics, opioids, etc.) should be assumed to have low GI motility, and stimulants should be prescribed more regularly (e.g., four times weekly, up to daily). Psyllium, although discussed in some guidelines,² is often less effective due to poor fluid intake and GI motility in older patients with PD.

Amanda should be advised to aim for having a Bristol 3 to 4 stool daily to ensure constipation is not affecting her appetite or levodopa absorption. PEG 3350 8.5 to 17 gm daily, along with sennosides 8.6 mg two tablets at bedtime if she has not had a good BM that day would be the recommended starting regimen. 

Other recommendations

Older adults with PD are at higher risk of fragility fractures.^15–17 Adequate dietary calcium intake (note calcium supplements are constipating) along with vitamin D supplementation should be routinely prescribed. Bone density screening is advised especially for those with falls. 

Summary/practice tips

1. PD is associated with non-motor symptoms including constipation, orthostatic hypotension, depression/anxiety and RBD. These can be readily identified upon routine screening. Make this a part of your practice! EMR use can support this type of tracking. 
2. OH should trigger reduction or discontinuation of BP meds, along with BP medication administration at bedtime and a focus on non-pharmacological measures. 
3. Antidepressants can exacerbate RBD, thus the lowest effective dose and administration in the daytime are advised. Melatonin dual action or extended release should be used as first line to manage RBD. 
4. Ask about BM frequency and texture with the goal of a Bristol 3- 4 stool daily. Avoid medications which exacerbate constipation, including anticholinergics and opioids. Treat constipation proactively with lifestyle measures, PEG regular dosing and PRN stimulants. 
5. Fragility fractures are common in PD. Vitamin D supplementation and adequate calcium intake should be advised routinely, and bone density screening performed. 

References

1. Connolly BS, Lang AE. Pharmacological Treatment of Parkinson’s disease . Jama. 2014;311(16):1670. doi:10.1001/jama.2014.3654
2. Guttman M, Slaughter PM, Theriault M, DeBoer DP, Naylor CD. Burden of parkinsonism: a population‐based study. Mov Disord. 2003;18(3):313-319.
3. GBD 2015 Neurological Disorders Collaborator Group VL, Abajobir AA, Abate KH, et al. Global, regional, and national burden of neurological disorders during 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Neurol. 2017;16(11):877-897. doi:10.1016/S1474-4422(17)30299-5
4. Seppi K, Ray Chaudhuri K, Coelho M, et al. Update on treatments for nonmotor symptoms of Parkinson’s disease—an evidence-based medicine review. Mov Disord. 2019;34(2):180-198. doi:10.1002/mds.27602
5. Aarsland D, Andersen K, Larsen JP, Lolk A. Prevalence and Characteristics of Dementia in Parkinson’s disease . Arch Neurol. 2003;60(3). doi:10.1001/archneur.60.3.387
6. Shulman LM, Taback RL, Rabinstein AA, Weiner WJ. Non-recognition of depression and other non-motor symptoms in Parkinson’s disease. Park Relat Disord. 2002;8(3):193-197. doi:10.1016/S1353-8020(01)00015-3
7. Ruffion A, Castro-Diaz D, Patel H, et al. Systematic Review of the Epidemiology of Urinary Incontinence and Detrusor Overactivity among Patients with Neurogenic Overactive Bladder. Neuroepidemiology. 2013;41(3-4):146-155. doi:10.1159/000353274
8. Postuma RB, Iranzo A, Hogl B, et al. Risk factors for neurodegeneration in idiopathic rapid eye movement sleep behavior disorder: A multicenter study. Ann Neurol. 2015;77(5):830-839. doi:10.1002/ana.24385
9. Onofrj M, Luciano AL, Thomas A, Iacono D, D’Andreamatteo G. Mirtazapine induces REM sleep behavior disorder (RBD) in parkinsonism. Neurology. 2003;60(1):113-115. doi:10.1212/01.WNL.0000042084.03066.C0
10. Winkelman JW, James L. Serotonergic antidepressants are associated with REM sleep without atonia. Sleep. 2004;27(2). doi:10.1093/sleep/27.2.317
11. Postuma RB, Gagnon JF, Tuineaig M, et al. Antidepressants and REM sleep behavior disorder: Isolated side effect or neurodegenerative signal? Sleep. 2013;36(11). doi:10.5665/sleep.3102
12. Wichniak A, Wierzbicka A, Walęcka M, Jernajczyk W. Effects of Antidepressants on Sleep. Curr Psychiatry Rep. 2017;19(9). doi:10.1007/S11920-017-0816-4
13. Tran TN, Vo TNN, Frei K, Truong DD. Levodopa-induced dyskinesia: clinical features, incidence, and risk factors. J Neural Transm. 2018;125(8). doi:10.1007/s00702-018-1900-6
14. Grimes D, Fitzpatrick M, Gordon J, et al. Canadian guideline for Parkinson’s disease . CMAJ. 2019;191(36):E989-E1004. http://www.cmaj.ca/content/191/36/E989
15. Invernizzi M, Carda S, Viscontini GS, Cisari C. Osteoporosis in Parkinson’s disease. Park Relat Disord. 2009;15(5). doi:10.1016/j.parkreldis.2009.02.009
16. Tan L, Wang Y, Zhou L, et al. Parkinson’s disease and risk of fracture: A meta-analysis of prospective cohort studies. PLoS One. 2014;9(4). doi:10.1371/journal.pone.0094379
17. Lee JY, Lim NG, Chung CK, Lee JY, Kim HJ, Park SB. Parkinson’s disease as risk factor in osteoporosis and osteoporotic vertebral fracture : Prevalence study using national inpatient sample database in Korea. J Korean Neurosurg Soc. 2019;62(1). doi:10.3340/jkns.2018.0012