The Treatment of Older Patients with Parkinson’s Disease

Background: There are approximately 150 000 persons over age 80 in Germany who suffer from Parkinson’s disease. Eighty percent of patients develop dementia during the course of this disease. Older patients with Parkinson‘s disease often suffer from the multimorbidity typically seen in this age group. Comorbidities affect the options for treating Parkinson’s disease. Older patients are markedly underrepresented in most trials of antiparkinsonian drugs.

Methods: In this narrative review, we propose practical ways to simplify the treatment regimen of older patients with Parkinson‘s disease to lessen side effects and make treatment more manageable for these patients and the persons caring for them.

Results: The mainstay of treatment is levodopa in combination with a dopa decarboxylase inhibitor, taken during the day as a standard-release or dispersible formulation and at night in extended-release form; along with a catechol-O-methyltransferase inhibitor if necessary. Antiparkinsonian drugs with other mechanisms of action should be used sparingly, if at all. Treatment options for patients with severe fluctuations in efficacy and long “off” (akinetic) phases include a jejunal levodopa pump and the subcutaneous administration of foslevodopa. Parkinson’s disease dementia should be treated with rivastigmine, a cholinergic anti-dementia drug (approved in capsule form for this indication). Otherwise intractable psychosis should be treated with quetiapine (off-label) or clozapine (evidence-based; weekly blood tests required). Other neuroleptic drugs should not be given to patients with Parkinson‘s disease. Physiotherapy and speech therapy are evidence-based components of therapy with proven efficacy in every stage of the disease.

Conclusion: Further randomized controlled trials tailored to this patient population are needed to provide a better evidence base for the treatment of older patients with Parkinson‘s disease.

Cite this as: Djukic M, Yoshida-Stiksrud E, Nau R: The treatment of older patients with Parkinson’s disease. Dtsch Arztebl Int 2025; 122: 412–8. DOI: 10.3238/arztebl.m2025.0083

Parkinson’s disease is characterized by a reduction and slowness of movement (bradykinesia) and at least one other symptom (resting tremor or rigor) (eTable). Geriatric patients are defined by an advanced age (predominantly 70 years and older) and the multimorbidity typically seen in this age group or by an age of 80 and older with an age-related increased vulnerability (e1). Geriatric treatment is provided to Parkinson patients whose illness began many years previously and who have therefore reached an advanced stage of the disease, as well as to patients who are diagnosed for the first time at an advanced age.

eTable

Common Parkinson’s syndromes in older patients

Disease prevalence increases with age (men/women between the ages of 80 and 84 2.86/2.02%, between 85 and 89 years 3.64/2.59%, and 90 years and older 3.92/2.57%). A total of around 310 000 individuals in Germany are affected by the illness, of which around 150 000 are aged 80 and older (e2).

Approximately 60% of patients in whom the diagnosis of Parkinson’s is made for the first time after reaching the age of 80 suffer from the akinetic-rigid phenotype. Parkinson’s symptoms, especially postural instability, is exacerbated by comorbidities common in old age, in particular polyneuropathy, disorders of vision, inner ear diseases, and sarcopenia (1, 2). The prevalence of orthostatic hypotension correlates with age. Pain, constipation, sleep disorders, and disturbed bladder function secondary to Parkinson’s disease are exacerbated by multimorbidity. Neuropsychiatric symptoms, such as apathy, depression, and anxiety are symptoms of Parkinson’s disease, but also occur frequently independent of it in older age. Around 80% of patients develop dementia in the course of the disease (3, 4, e3). A large number of elderly patients with Parkinson’s disease receive polypharmacy (≥ 5 prescription drugs) or hyperpolypharmacy (≥ 10 prescription drugs) (e4).

With increasing duration of the disease, serious impairments are to be expected from the side effects of Parkinson’s medication and the disease itself, for example, daytime fatigue, obsessive-compulsive disorder, confusion, or predominantly optic hallucinations. Fluctuations in drug action become increasingly uncontrollable. Orthostatic hypotension and disorientation, delusions, and visual hallucinations are not just related to high drug dosages (5). Around 50% of patients with Parkinson’s disease report present or previous hallucinations (5), while daytime fatigue and orthostatic hypotension are even more common (2).

Methods

The aim of the present narrative review is to summarize the available forms of treatment for Parkinson’s disease in the specific context of older patients. We conducted a search of the literature in PubMed using the search terms “parkinson’s disease” and “randomized trial” and “old age” (n = 41) or “geriatric” (n = 198) as well as the search terms “parkinson’s disease” and “old age” or “geriatric” together with individual drug names. We also looked at the pharmacokinetics and dynamics of the drugs used to treat Parkinson’s disease, with a focus on the special features related to old age. The search terms were individual drug names and “pharmacokinetics” and “old age” or “geriatric”. Currently, there is a paucity of randomized controlled trials covering more evidence-based treatment of older patients with Parkinson’s disease (e5).

Pharmacologic therapy with levodopa

Tables 1–3 and the Figure provide an overview of the drugs available for the treatment of Parkinson’s disease, their pharmacokinetics, and randomized trials.

Figure

Effect/side effect ratio

Levodopa

The amino acid levodopa is only used in combination with a decarboxylase inhibitor (benserazide or carbidopa) because otherwise it is subject to rapid metabolization. Such combinations have the most favorable effect/side effect ratio, regardless of patient age. Because levodopa-induced dyskinesia can develop after about five years, an attempt to first start with less effective drugs is made in younger patients. This risk is accepted when treating older patients (6, 7).

Pharmacokinetics

The elimination half-life (t½) of a single oral dose of levodopa administered together with a decarboxylase inhibitor is around 1.8 hours in older patients (8). The pharmacokinetics of levodopa is influenced by gastric emptying which can be delayed in Parkinson’s disease (9). The time to reach peak plasma concentration of levodopa after oral administration varies interindividually and intraindividually and ranges between 0.5 and two hours (8).

Levodopa doses taken together with a (protein-rich) meal may be less effective (protein akinesia) (10, 11, 12). The person undergoing treatment should follow standardized medication regimens in relation to meals (levodopa at least 30 minutes before or 60 minutes after a meal). Certain medications can alter levodopa absorption (13) (Table 2).

Table 2

Factors influencing the pharmacokinetics of levodopa plus decarboxylase inhibitor

Tablets designed to dissolve, whether suspended or undissolved, result in faster absorption of levodopa and decarboxylase inhibitor as compared with conventional tablets and capsules. Extended-release preparations of levodopa plus a decarboxylase inhibitor result in a slower rise of levodopa levels and a delayed fall in serum concentration (14). Extended-release levodopa preparations are not recommended for daytime use due to their lower and more variable bioavailability. But daytime administration of extended-release levodopa in patients with uncontrolled motor fluctuations or dyskinesia may be suitable for extending the periods of good mobility in the absence of dyskinesia (e6, e7).

Inhaled levodopa shortens the time between ingestion and reaching peak levels as compared with oral levodopa (15, 16). The inhalation powder contains only levodopa. It is only used for akinetic periods in patients being treated simultaneously with levodopa and a decarboxylase inhibitor. Any advantage over soluble levodopa for older patients is still uncertain. There is a considerable need for the training of older patients in the correct handling of inhalers (17).

Pharmacodynamics

In the early stages of Parkinson’s disease, fluctuations in the action of levodopa are minimal, despite large variations of plasma concentrations. After a treatment period with levodopa of around five years, fluctuations in its effect develop which are related to fluctuations in plasma levels (8, 9, 18). With a long-term disease course, levodopa plasma concentrations must therefore be kept as constant as possible at times when the patient is awake.

Dose finding

The amount of each single dose and dose intervals are titrated to individual patient needs (8). In the early stage of the disease, a three-times-daily dosing schedule is often chosen. The dose interval can be shortened and/or levodopa elimination slowed down in patients with advanced Parkinson’s disease (11). As the disease progresses, the minimum plasma concentration of levodopa required to improve mobility increases, thus requiring sufficiently high individual doses. (19).

In severely affected patients, the first morning dose and any interim medication taken as needed during off-phases are administered as a soluble tablet taken in dissolved form. (20, 21). Patients with an advanced stage of the disease are given an extended-release preparation for the night (22). Some of these patients require a further dose of levodopa during the night (2–4 o’clock).

Treatment options for motor complications

Catechol-O-methyltransferase inhibitors

Catechol-O-methyltransferase (COMT) inhibitors are used in combination with levodopa to prolong the effects of levodopa. The usual COMT inhibitors entacapone and opicapone hardly penetrate the central nervous system (CNS)(23). They scarcely cause any CNS side effects beyond those associated with elevated plasma levels of levodopa. This allows their use in older patients with Parkinson’s disease (Tables 1 and 3). The most common side effect is dyskinesia secondary to elevated plasma levels of levodopa (24).

Entacapone is administered together with levodopa because of its short half-life of around 2.5 hours. Combination preparations with levodopa (+ decarboxylase inhibitor) simplify treatment. Entacapone causes the urine to turn a reddish color which can alarm some patients (25, e8). Opicapone also has a short half-life. The opicapone-COMT complex remains stable for a long time, so that COMT activity still presents a decrease of approximately 65% after 24 hours (25, e9). Opicapone 50 mg is therefore taken once daily at least one hour before or after levodopa before going to sleep. Tolcapone can cause rare liver damage (25) and should be avoided in older patients (e10).

Dopamine-antagonists and monoamine oxidase inhibitors

Both substance classes have an unfavorable effect/side effect ratio in the majority of older patients (6) (Figure). Common side effects of both substance classes are listed in Table 1.

Table 1

Overview of available treatment

In an open randomized study comparing dopamine agonists with MAO-B or COMT inhibitors in patients inadequately controlled on levodopa, patient-rated quality of life was better with a MAO-B inhibitor as adjuvant therapy than with COMT inhibitors (e11). The treatment discontinuation rate was lowest for COMT inhibitors.

Amantadine, MAO-B inhibitors (selegiline, rasagiline, and especially safinamide) (e12), and dopamine agonists (pramipexole, ropinirole, piribedil, and rotigotine) are usually not recommended for older patients, mainly because of the risk of developing psychosis and orthostatic dysregulation. Rotigotine is administered via a transdermal patch, may be immediately removed should side effects develop, and appears to be better tolerated than other dopamine agonists (e13). However, rotigotine is also only recommended to a limited extent especially for palliative purposes at the end of life (e14, e15). The scale of side effects from dopamine agonists and MAO-B inhibitors in patients over 80 has not been sufficiently assessed (e16).

Levodopa therapy via a nasogastric tube, percutaneous gastroenterostomy, and percutaneous jejunal tube

Intravenous levodopa medications are not available for routine clinical use (e17). Patients with Parkinson’s disease who (occasionally) cannot swallow receive their medication via a nasogastric or percutaneous nasogastric tube (see [2] for more information about the possibility of administering various preparations via enteral tubes). A nasogastric tube can be lifesaving when Parkinson’s symptoms deteriorate, for example, as a result of an infection (26). Percutaneous tubes are usually tolerated in the long-term if they are correctly secured.

Should unpredictable fluctuations in levodopa plasma concentrations develop, then the jejunal administration of levodopa plus a decarboxylase inhibitor via an infusion pump can ensure constant levodopa plasma concentrations (27) (eFigure). Pump therapy can also be used in patients with dementia. Entacapone is also suitable for continuous jejunal infusion together with levodopa/carbidopa (e18). It reduces the required infusion volume (28).

eFigure

Plasma concentrations of levodopa and carbidopa

Subcutaneous pump systems

Foslevodopa/foscarbidopa (ratio of 20:1) has been available since 2023 for continuous subcutaneous application. Its administration is similar to that of an apomorphine pump which should not be used in older patients due to potential psychiatric side effects (29, e19). Complications primarily include erythema, nodules, and edema or infection at the puncture site. Since subcutaneous infusion is not invasive, the importance of this form of treatment in older patients will most likely increase (e20).

Deep brain stimulation

The indication for deep brain stimulation (DBS) include side effects and variations of efficacy of dopaminergic therapy (e21). Because cognitive deficits can significantly deteriorate, and personality changes (for example, depressions) can develop postoperatively (e22), this method should only be considered for older patients in exceptional cases (e23).

Unsuitable drugs

Not only high-potency classical neuroleptics, but also drugs usually classified as atypical neuroleptics (with risperidone as the lead compound), as well as low-potency sedating and sleep-inducing neuroleptics (lead compounds melperone, pipamperone, prothipendyl), metoclopramide, and in rare case other medications, for example flunarizine, lithium, valproate can exacerbate Parkinson’s symptoms or cause drug-induced parkinsonism (e24). The use of antipsychotics increase mortality in patients with Parkinson’s disease. In a retrospective case-control study involving 7877 matched pairs of patients (age 76.3 ± 7.7 years, mean age ± standard deviation, 99.2% men) this risk was higher for haloperidol (hazard ratio 4.8), risperidone (2.6), and olanzapine (2.8) than for quetiapine (1.9), while there was not sufficient data available for clozapine (30). All other measures must be fully exhausted before using neuroleptics in patients with Parkinson’s disease (Table 3, Box 1).

Box 1

Treatment of hallucinations brought on by Parkinson’s disease

Table 3

Randomized clinical trials on the pharmacotherapeutic treatment of older patients with Parkinson’s disease

Treatment options for other complications

Parkinson’s disease psychosis

Older patients with Parkinson’s disease have a high risk (30–40%) of developing psychosis (Table 3, Box 1) (31). Mild cognitive impairment or dementia, advanced age, duration and severity of the Parkinson’s disease, loss of sight or hearing, as well as psychiatric and medical comorbidities increase this risk (30). The occurrence of hallucinations, even when initially mild and with preserved insight, may indicate initial psychotic development. With hallucinations or delusions, treatment should preferably be limited to levodopa (if necessary, in combination with a COMT inhibitor) (Figure).

Clozapine is the only approved antipsychotic whose effect without worsening of motor function has been demonstrated in randomized trials (32, 33, 34). White blood count and neutrophilic granulocytes must be checked on a weekly basis due to the risk of developing agranulocytosis. Quetiapine also does not worsen motor function but was not reliably effective in randomized trials (30, e25, e26). It is often used “off label” for Parkinson’s disease.

Akinetic crisis

Possible causes such as dehydration or infection should be treated first. Levodopa is administered via a nasogastric tube. The precondition is preserved gastrointestinal motility (auscultation of the abdomen, adequate transport of administered fluids via the nasogastric tube, sufficient defecation frequency). A case study has shown the effectiveness of foslevodopa as a subcutaneous infusion for akinetic crisis in the absence of a nasogastric tube (e27).

The glutamate antagonist amantadine is available in intravenous form and can improve motor function in an emergency secondary to akinetic crisis. It accumulates rapidly if renal function is impaired (e28). Its use requires comprehensive monitoring in older patients.

Parkinson’s disease dementia

Cholinergic antidementia drugs are effective for dementia associated with Parkinson’s disease (7, 35). Of the cholinergic anti-dementia drugs, only rivastigmine as a hard capsule is approved for Parkinson’s disease dementia. The somewhat better-tolerated rivastigmine patch is an off-label use in Parkinson’s disease dementia (7, 35). Although rivastigmine was associated with nausea, vomiting, diarrhea, and increased tremor, it did reduce the incidence of hallucinations and orthostatic dysregulation in patients with Parkinson’s disease (35). Another point in favor of cholinergics is their life-prolonging effect, which is somewhat more pronounced in patients with Parkinson’s disease than in those with Alzheimer’s (risk ratio 0.56 and 0.64 in comparison with no cholinergic drug) (36).

Cholinesterase inhibitors reduce the incidence of falls in patients with Parkinson’s disease by around 50% (37). This was also true in a randomized trial for patients without dementia (38) (Table 3).

In a small randomized trial, memantine (not approved in Germany either for Parkinson’s disease dementia or for Parkinson’s disease) improved postural instability but not gait (e29). In Parkinson’s disease dementia and dementia with Lewy bodies, it shortened reaction time to visual yes/no stimuli by an average of 130 ms and improved performance in the immediate and delayed word recognition test by an average of 3% and 5%, respectively, (e30).

Continence impairment

A number of anticholinergics for reducing detrusor activity within the bladder have adverse CNS effects. Trospium is a urinary antispasmodic drug with the least CNS penetration and the fewest cognitive side effects due to its hydrophilic properties (39). Anticholinergics with relatively specific action on muscarinergic M3 receptors are also supposed to cause minor CNS side effects (e31).

Treatment for autonomic nervous system disorders

Reduced bowel motility associated with constipation and orthostatic hypotension are caused by the underlying disease and pharmacologic therapy. Constipation is treated as long as possible with a high-fiber diet and adequate fluid intake, movement exercises, physiotherapy, and osmotic laxatives (for example, macrogol) or/and probiotics (40). Rivastigmine has a prokinetic effect on the gastrointestinal tract (35).

Orthostatic dysregulation (Box 2) is treated with lower limb compression therapy (e32). Leg muscle training, for example, running on the spot, cycling as well as cold showers and alternating baths, help tone the leg vessels and reduce the degree of orthostatic dysregulation (e33). All antiparkinson drugs, especially dopamine agonists, and clozapine can worsen orthostatic hypotension (e34).

Box 2

Treatment of symptomatic orthostatic dysregulation in Parkinson’s disease

Apart from promoting intestinal motility, antidopaminergic drugs also have a positive effect on orthostatic dysregulation. Metoclopramide is contraindicated in Parkinson’s disease due to its blockade of dopamine receptors in the central nervous system. In a British cohort study involving 5114 patients with Parkinson’s disease (mean age 74.5 years, total mortality 7.4%/year), the use of domperidone, which hardly crosses the blood-brain barrier, was associated with a doubling of total mortality (e35).

Sympathomimetic drugs, for example, midodrine, etilefrine, can be administered short-term to raise blood pressure and treat orthostatic dysregulation, yet with limited success (40, e36, e37).

Droxidopa, an oral norepinephrine precursor (only available in Germany through international pharmacies), improves orthostatic dysregulation at a dose of 100 to 600 mg, three times daily, in various neurodegenerative diseases, including Parkinson’s (40, e38).

The effect of mineralocorticoids is to increase blood pooling. They cannot be used in the majority of older patients due to potential concomitant heart failure.

Summary

In older patients with Parkinson’s disease, treatment regimens are often too complex and so produce avoidable side effects without providing any real benefit to the patients. Studies on the effect of antiparkinson therapy in patients aged 80 and older are very rare. Simplifying the treatment by changing to levodopa plus a decarboxylase inhibitor, possibly in combination with a COMT inhibitor and the cholinergic drug rivastigmine, can improve motor, cognitive, and autonomic symptoms in the later stages. Therapeutic nihilism is also inappropriate for severely ill older patients with Parkinson’s disease. Improvement in the quality of life can be achieved by the intervention of specialists in the treatment of Parkinson’s disease (e39). Non-pharmacological therapy (eSupplement) is just as important as pharmacotherapy in preventing admission to a nursing home and confinement in bed.

Acknowledgments
We would like to thank Prof. Martin Wehling, emeritus director of the Institute for Clinical Pharmacology of the Faculty for Clinical Medicine of Mannheim of the Heidelberg University, for his permission to modify the Figure published in his book “Drug therapy for the elderly” (6).

Conflict of interest statement
The authors declare that there are no conflicts of interest.

Manuscript received on 11 November 2024, revised version accepted on 5 May 2025

Translated from the original German by Dr. Grahame Larkin

Corresponding author:
Prof. Dr. Roland Nau

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