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Parkinson’s disease (PD) is a chronic, progressive movement disorder
resulting from loss of dopamine from the nigrostriatal tracts in the brain,
and is characterized by rigidity, bradykinesia, postural disturbances, and
Treatment for PD is aimed at restoring dopamine supply through one, or
a combination, of the following methods: exogenous dopamine in the
form of a precursor, levodopa; direct stimulation of dopamine receptors
via dopamine agonists; and inhibition of metabolic pathways responsible
Therapy for PD is usually delayed until there is a significant effect on
quality of life; generally younger patients start with dopamine agonists or
monoamine oxidase type B (MAO-B) inhibitors, whereas older patients
Initial therapy with levodopa-sparing agents is associated with a lower
risk of developing motor complications than with levodopa, but all
patients will eventually require levodopa.
Advanced PD is characterized by motor fluctuations including a gradual
amantadine can improve dyskinesias. Deep brain stimulation of the
globus pallidus interna or subthalamic nucleus may benefit patients with
Antioxidants, dietary supplements, and other investigational therapies
have been studied for the management of Parkinson’s disease.
Comprehensive therapy for patients should include attention to many
progressive complications of PD, including neuropsychiatric
disturbances and autonomic dysfunction.
RLS is a disabling sensorimotor disorder typically marked by irresistible
urge to move the legs (akathisia). It is often associated with
uncomfortable paresthesias or dysesthesias and often occurs in the
Several conditions are associated with or can aggravate RLS. Periodic
limb movements of sleep (PLMS) is not the same as RLS but often
Dopamine agonists are first-line treatments for RLS. They are preferred
because they are longer acting than levodopa, and reduce symptoms
throughout the entire night. Other effective therapies include
carbidopa/levodopa, gabapentin, benzodiazepines, and opiates.
A common problem with long-term use of dopaminergic agents in RLS,
particularly levodopa, is an augmentation effect. This refers to a gradual
dosage intensification that occurs in response to a progressive
worsening of symptoms after an initial period of improvement. Gradual
withdrawal of therapy and substitution with other agents should be
performed, rather than continued dopaminergic dose escalation.
Essential tremor should be distinguished clinically from tremor associated
Treatments of choice for essential tremor include propranolol or
primidone. In refractory cases, targeted botulinum toxin A injections can
Incidence, Prevalence, and Epidemiology
PD is a chronic, progressive movement disorder first described in 1817 by Dr.
James Parkinson. Since that time, the term parkinsonism has come to refer to any
disorder associated with two or more features of tremor, rigidity, bradykinesia, or
1 Most cases of PD are of unknown cause and referred to as
idiopathic parkinsonism; however, viral encephalitis, cerebrovascular disease, and
hydrocephalus have symptoms similar to PD as part of their clinical presentation.
Unless otherwise stated, all references to PD in this chapter refer to the idiopathic
The age at onset of PD is variable, usually between 50 and 80 years, with a mean
2 Both the incidence and prevalence of PD are age-dependent, with
annual incidence estimates ranging from 10 cases/100,000 (age 50–59 years) to 100
cases/100,000 (age 80–89 years) and an estimated prevalence of 1% of the
population older than 65 years of age.
4 Men are affected slightly more frequently
3 Despite the availability of effective symptomatic treatments to improve
both quality of life and life expectancy, no cure exists. The symptoms of PD are
progressive, and within 10 to 20 years, significant immobility results for most
5 More rapid rates of symptom progression and motor disability have been
observed in patients of older age at disease onset.
6 PD itself does not cause death;
however, patients often succumb to complications related to impaired mobility and
function (e.g., aspiration pneumonia, thromboembolism) and overall frailty.
The etiology of PD is poorly understood. Most evidence suggests it is multifactorial
and attributable to a complex interplay between age-related changes in the
nigrostriatal tract, underlying genetic risks, and/or environmental triggers. Support
for this hypothesis can be found in several historic observations. Notably, the
postviral parkinsonian symptoms occurring after epidemics of encephalitis in the
early 1900s, and the discovery that ingestion of a meperidine analog, 1-methyl-4-
phenyl-1,2,3,6-tetrahydropyridine (MPTP), by heroin addicts in northern California
during the early 1980s caused a rapid and irreversible parkinsonism via the
oxidation of free radicals during metabolism by the MAO-B enzyme.
For an excellent in-depth discussion of the importance of the MPTP discovery and its influence on PD
program Frontline at http://www.pbs.org/wgbh/pages/frontline/parkinsons/.
The relative contributions of environment and genetics to the occurrence of PD
remain controversial; rural living, pesticide exposure, and consumption of well
water have consistently been associated with increased lifetime risk of PD, whereas
cigarette smoking and caffeine ingestion appear to be protective.
several genes, including α-synuclein (SNCA), leucine-rich repeat kinase-2 (LRRK2),
parkin, PTEN- induced kinase-1 (PINK1), and DJ-1, have been observed in rare
familial inherited cases of PD, but these genes lack typical Mendelian patterns of
inheritance, and do not account for the threefold increased risk of developing PD for
individuals who have a first-degree relative affected with sporadic PD.
advances in molecular genetics and genome-wide association studies have revealed
other novel risk genes; however, the exact linkage between genetics, environment,
and clinical expression of disease remains uncertain.
The salient features of PD result from a loss of dopaminergic neurons in the
nigrostriatal tracts of the brain and development of abnormal intraneuronal protein
aggregates called Lewy bodies that interfere with neuronal function. The nigrostriatal
tracts are neuronal tracts between the substantia nigra and the striatum. They are part
of the extrapyramidal system of the brain involving the basal ganglia. This area is
involved with maintaining posture and muscle tone by regulating voluntary smooth
muscle activity. The pigmented neurons within the basal ganglia have dopaminergic f
ibers, and in PD, these dopamine-producing neurons are progressively depigmented.
The remaining dopaminergic-producing cells have been shown (in postmortem
examination) to contain Lewy bodies.
11 Lewy body pathology appears to ascend the
brain in a predictable manner in PD, beginning in the medulla oblongata in
preclinical stages (which may explain observations of anxiety, depression, and
olfactory disturbance), ascending to the midbrain (motor dysfunction), and spreading
eventually to the cortex (cognitive and behavioral changes).
neurons, either from death or from dysfunction, results in loss of dopamine-mediated
inhibition of acetylcholine neurons. In PD, the typical balance of dopamine and
acetylcholine is lost, resulting in a relative increase in cholinergic activity.
The exact pathologic sequence leading to neurodegeneration is unclear, but free
radicals formed as by-products of dopamine auto-oxidation have been implicated.
The finding that a critical threshold of neuronal loss (at least 70%–80%) occurs
before PD becomes clinically apparent suggests that adaptive mechanisms (e.g.,
upregulation of dopamine synthesis or downregulation of synaptic dopamine
reuptake) may somehow influence disease progression during the preclinical stages.
Clinical Presentation of Parkinson’s Disease
Laboratory values and vitalsigns obtained at this visit include the following:
Thyroid stimulating hormone, 3.65 microunits/L
White blood cells, 4,400 cells/μL
The foundation for establishing the diagnosis of PD remains firmly grounded in
obtaining a careful history and physical examination.
11 The neurologic examination to
assess motor function, along with a positive response to levodopa, is highly
diagnostic. The search for biomarkers of premotor PD in blood, cerebrospinal fluid,
and urine has not uncovered single, practical candidates that are sensitive and
9 Likewise, although imaging techniques can visualize nigrostriatal nerve
terminals of dopamine synthesis and identify presymptomatic pathology, their use
remains investigational, and routine use in asymptomatic, at-risk individuals is not
yet justified. Other associated premotor symptoms, such as hyposmia (a reduced
ability to smell and detect odors), rapid eye movement (REM) sleep disorder, and
softening and tonal changes of the voice are among the earliest symptoms to appear;
screening for these findings may prove more economically practical in identifying a
high risk population worthy of further diagnostic evaluation.
advancements, the diagnosis of PD may rely on clinical, imaging, genetic, and a panel
of laboratory biomarker data. However, by the time patients such as L.M. present
with symptoms, a substantial burden of neuropathologic evidence has accumulated,
and therefore, a diagnosis can be made clinically, without the need for further
laboratory or radiologic testing.
The classic features of PD—tremor, limb rigidity, and bradykinesia—are easily
recognized, particularly in advanced stages of disease. Limb rigidity and
bradykinesia are direct consequences of dopamine loss; by disinhibiting cholinergic
transmission, dopamine loss indirectly causes tremor. It is important to note that not
all classic features are required to make the diagnosis of PD. The presence of two or
more features indicates clinically probable PD.
14 Tremor, which is most often the
first symptom observed in younger patients, is usually unilateral on initial
presentation. Frequently, the low-amplitude tremor is of a pill-rolling type involving
the thumb and index finger (3–6 Hz); it is present at rest, worsens under fatigue or
stress, and is absent with purposeful movement or when asleep.
distinguish it from essential tremor, which usually manifests as a symmetric tremor in
the hands, often accompanied by head and voice tremor.
patients with PD do not present with tremor.
11 Muscular rigidity resulting from
increased muscle tone often manifests as a cogwheel or ratchet (catch-release) type
of motion when an extremity is moved passively.
1 Rigidity may also be experienced
as stiffness or vague aching or limb discomfort.
11 Bradykinesia refers to an overall
slowness in initiating movement. Early in the disease, patients may describe this as
weakness or clumsiness of a hand or leg.
11 Because the disease progresses, difficulty
initiating and terminating steps results in a hurried or festinating gait; the posture
becomes stooped (simian posture), and postural reflexes are impaired.
that were unilateral on initial presentation progress asymmetrically and often become
bilateral and more severe with disease progression.
1 Patients with PD may develop
masked facies, or a blank stare with reduced eye blinking (Figure 59-1).
Basic Nursing. 7th ed. Philadelphia, PA: Lippincott-Raven; 1999:1063.)
Because the diagnosis of PD is clinical, misdiagnosis can occur, leading to
inappropriate, ineffective, or delayed treatment. Several conditions can be mistaken
for PD and are important to distinguish from PD because they respond poorly to
dopaminergic medications and are associated with worse prognosis.
dementia early in the disease, symmetric parkinsonism, wide-based gait, abnormal
eye movements, marked orthostatic hypotension, urinary retention, or marked
disability within 5 years after the onset of symptoms suggests alternative diagnoses to
11 Drugs may also mimic idiopathic PD. Drugs that act as antagonists at
receptors (e.g., neuroleptics, prochlorperazine, and
metoclopramide), and others such as valproate, amiodarone, phenytoin, and lithium
may cause a state of drug-induced parkinsonism. This should be excluded before the
diagnosis of PD is established. Although generally reversible, symptoms may persist
for weeks or months after discontinuation of the offending agent.
L.M. initially presents with classic premotor features such as his soft, monotone
voice and reduced sense of smell, in addition to classic symptoms of PD. A
noticeable unilateral resting tremor is present along with decreased manual dexterity,
as evidenced by his difficulty handling a paintbrush. Handwriting abnormalities
occur frequently, particularly micrographia, a symptom of bradykinesia. Because
L.M. is an artist, this abnormality would be particularly troublesome. Rigidity
(ratcheting of the arms) and a mask-like facial expression also are present. Although
he has a partially stooped posture, it is difficult to attribute this entirely to the disease
because postural changes commonly occur with advancing age and, on physical
examination, his balance was normal. To confirm the diagnosis of PD, a therapeutic
trial of medication (levodopa) may be considered. A positive response to levodopa,
as evidenced by an improvement in motor function, suggests the diagnosis of PD.
However, patients with the tremor-predominant form of the disease may not respond
to levodopa, especially in the early stages of the disease.
Staging of Parkinson’s Disease
CASE 59-1, QUESTION 2: What are the stages of PD? In what stage of the disease is L.M.?
To assess the degree of disability and determine the rate of disease progression
relative to treatment, various scales have been developed. The most common of these
is the Hoehn and Yahr scale ( Table 59-1).
In general, patients in Hoehn and Yahr
stage 1 or 2 of PD have mild disease that does not interfere with activities of daily
living (ADLs) or work and usually requires minimal or no treatment. In stage 3
disease, daily activities are restricted and employment may be significantly affected
unless effective treatment is initiated. According to the scale, L.M. appears to be in
late stage 2, early stage 3 of the disease.
With advanced-stage disease (3, 4), most patients require a double or triple drug
therapy strategy. Patients with end-stage disease (stage 5) are severely incapacitated
and, because of advanced disease progression, often do not respond well to drug
Treatment of Parkinson’s Disease
Numerous national and international guidelines exist regarding the management of
motor and nonmotor symptoms of PD. These guidelines include the American
Academy of Neurology (AAN) Practice Parameters developed in 2002 and 2006,
the United Kingdom National Institute for Health and Care Excellence (NICE)
National Guideline developed in 2006 and revised in July 2017,
Federation of Neurological Societies Movement Disorder Society-European Section
(EFNS MDS-ES) Guidelines developed in 2013
; all are cited throughout the text.
Staging of Disability in Parkinson’s Disease (PD)
Stage 1 Unilateral involvement only; minimal or no functional impairment
Stage 2 Bilateral involvement, without impairment of balance
Stage 4 Severely disabled, cannot walk and stand unassisted; significantly incapacitated
Stage 5 Restricted to bed or wheelchair unless aided
Although most of this chapter is devoted to the drug therapy of PD, the importance
of nonpharmacologic, supportive care cannot be overemphasized. Exercise, physical
and occupational therapy, and good nutritional support can be beneficial at the earlier
stages to improve mobility, increase strength, and enhance well-being and mood.
Psychological support is often necessary in dealing with depression and other related
problems. Newly diagnosed patients and their family members need to be educated
about what to expect from the disease and the various forms of treatment available.
The support of family members is vital in establishing an overall effective
Nonpharmacologic therapy should continue throughout the course of care;
however, due to the progressive nature of PD, pharmacologic therapy is often
necessary. Because the salient pathophysiologic feature of PD is the progressive loss
of dopamine from the nigrostriatal tracts in the brain, drug therapy for the disease is
aimed primarily at replenishing the supply of dopamine. This is accomplished
through one, or a combination, of the following methods: (a) administering exogenous
dopamine in the form of a precursor, levodopa; (b) stimulating dopamine receptors
within the striatum through the use of dopamine agonists (e.g., pramipexole,
ropinirole); or (c) inhibiting the major metabolic pathways within the brain that are
responsible for the degradation of levodopa and its metabolites. This latter effect is
achieved through the use of aromatic L-amino acid decarboxylase (AAD) inhibitors
(e.g., carbidopa), COMT inhibitors (e.g., entacapone), or MAO-B inhibitors (e.g.,
selegiline, rasagiline). Anticholinergics are also used; however, they are solely
efficacious for the cholinergic-mediated tremor, and their routine use is limited by
central nervous system (CNS) adverse effects, particularly in older patients. A
unique agent, amantadine, is also used occasionally and may provide modest benefits
via both dopaminergic and nondopaminergic (inhibition of glutamate) mechanisms
(Table 59-2). Because PD progresses, additional options, such as surgery, may be
appropriate for a subset of patients.
Despite optimization of both pharmacologic and nonpharmacologic therapies in
PD, physical disability is progressive and unavoidable. In many instances, adverse
effects of the medications themselves can lead to additional problems. These include
neuropsychiatric problems (e.g., cognitive impairment and dementia, hallucinations
and delirium, depression, agitation, anxiety), autonomic dysfunction (e.g.,
constipation, urinary problems, sexual problems, orthostasis, thermoregulatory
imbalances), falls, sleep disorders (e.g., insomnia or sleep fragmentation,
nightmares, RLS), and motor complications (e.g., disabling periods of either too
much [dyskinetic] or too little [akinetic] dopaminergic activity). In general, the more
efficacious medications are also those with the greatest risk of serious side effects
Medications Used for the Treatment of Parkinson’s Disease (PD)
Name Dosage Unit Titration Schedule Usual Daily Dose Adverse Effects
10 mg/mL injection Initial 2-mg
Rotigotine (Neupro) 1,-, 2-, 3-, 4-, 6-, 8-
4–6 mg/24 hour Hallucinations,
200-mg tablet 200 mg with each
Tolcapone (Tasmar) 100-mg tablet 100 mg TID 300–600 mg divided
Monoamine Oxidase Type B (MAO-B) Inhibitors
5-mg tablet, capsule 5 mg every morning;
5–10 mg/day Insomnia, dizziness,
1.25-mg tablet 1.25 mg every day;
Rasagiline (Azilect) 0.5-, 1-mg tablets 0.5–1 mg once daily 0.5–1 mg/day Similar to selegiline
50-, 100 mg tablets 50 mg once daily;
50-100 mg/day Similar to selegiline
aA transdermal formulation is also available, but not approved for use in PD.
BID, twice daily; COMT, catechol-O-methyltransferase; MAO-B, monoamine oxidase type B; ODT, orally
disintegrating tablet; QID, four times daily; TID, three times daily.
Treatment of Early Parkinson’s Disease
CASE 59-1, QUESTION 3: When should L.M. begin treatment for his PD?
In choosing when to treat the symptoms of PD and which therapy to use, care must
be taken to approach each patient individually. Although no consensus has been
reached about when to initiate symptomatic treatment, most healthcare professionals
agree that treatment should begin when the patient begins to experience functional
impairment as defined by (a) threat to employment status, (b) symptoms affecting the
dominant side of the body, or (c) bradykinesia or rigidity.
preferences also should be considered. Judging by the symptoms L.M. is displaying,
he would likely benefit from immediate treatment. His symptoms are unilateral but
are occurring on his dominant side and are interfering with his ability to paint, thus
affecting his livelihood. He is also showing signs of rigidity and bradykinesia but can
otherwise live independently. An algorithm for the management of patients with early
PD is presented in Figure 59-2. The long-term, individualized treatment plan is
usually characterized by frequent dosage adjustments because of the chronic and
progressive nature of the disease.
with a levodopa or levodopa-sparing therapy?
Despite advances in pharmacologic treatment options for PD, no therapy has been
proven to be disease-modifying or neuroprotective. Therapy continues to be
symptomatic, and levodopa remains the most effective antiparkinsonian agent.
However, the question of when to begin levodopa in the treatment of PD has been
historically debated. With long-term use, the efficacy of levodopa decreases and risk
for the development of motor fluctuations and dyskinesias increases. Because
escalating doses of levodopa are accompanied by a high frequency of undesirable
side effects, other methods of enriching dopamine supply have been developed. Two
such methods include the use of dopamine agonists and MAO-B inhibitors. Both of
these modalities have proven efficacy early in the disease.
Dopamine agonists, which bind directly to dopamine receptors, do not require
metabolic conversion to an active product and therefore act independently of
degenerating dopaminergic neurons. In clinical trials comparing dopamine agonists
with levodopa, ADLs and motor features are improved to a greater degree with
levodopa compared with dopamine agonists.
18 Although they are not as effective as
levodopa, the dopamine agonists have potential advantages. Unlike levodopa,
circulating plasma amino acids do not compete with dopamine agonists for
absorption and transport into the brain, eliminating administration constraints.
Dopamine agonists have a longer half-life than levodopa formulations, reducing the
need for multiple daily dosing. As a class, dopamine agonists provide adequate
control of symptoms when given as monotherapy in up to 80% of patients with earlystage disease.
Short- and long-term comparisons of patients with early disease started on either
levodopa or dopamine agonists have varying results. In trials extending 4 to 5 years,
therapy with dopamine agonists is associated with fewer motor complications such
as dyskinesias, delayed time to dyskinesias, and delayed need for initiation of
22–24 Against levodopa as initial therapy, early trials of the
dopamine agonists appear to delay the onset of dyskinesias. In a randomized,
controlled trial evaluating the development of motor complications with levodopa or
the dopamine agonist pramipexole, 301 untreated patients with early PD were
randomly assigned to receive either pramipexole 0.5 mg 3 times daily or
carbidopa/levodopa 25/100 mg 3 times daily.
24 Patients in both arms could be
prescribed open-label levodopa as needed for disability during the maintenance
phase of the study. After a mean follow-up of 24 months, fewer pramipexole-treated
patients reached the primary endpoint of time to the first occurrence of wearing-off,
dyskinesias, or on–off motor fluctuations (28% vs. 51%; P<0.001) than the patients
initially randomly assigned to levodopa therapy. Additionally, patients in the
pramipexole group were receiving lower daily doses of levodopa, theoretically
conferring a reduced risk of developing motor complications. Long-term follow-up
of this cohort (mean = 6 years) revealed a persistently lower rate of dopaminergic
motor complications in the pramipexole-treated patients compared with those
receiving levodopa (50% vs. 68.4%, respectively; P = 0.002).
Figure 59-2 Suggested treatment algorithm for the management of early PD.
Despite the continued increased risk of motor complications in patients started on
levodopa, trials extending 10 to 15 years found no significant difference in disease
severity rating or rates of disabling dyskinesias.
27 Patients treated initially with
ropinirole were less likely to experience dyskinesias compared with those treated
initially with levodopa at the end of a 5-year evaluation.
group used lower mean daily doses of levodopa (427 mg vs. 753 mg) but were
almost twice as likely to need open-label levodopa supplementation (66% vs. 36%).
Dyskinesias developed in 20% of the ropinirole-treated patients compared with 45%
of the levodopa-treated patients. For ropinirole-treated patients who were able to
remain on monotherapy without open-label levodopa supplementation, only 5%
experienced dyskinesia, compared with 36% of those receiving levodopa
monotherapy. Although the lower incidence of dyskinesias was shown to persist in a
long-term open-label follow-up of this study cohort, there was no difference in
disease severity between the ropinirole-treated group and the levodopa-treated group
in part to the fact that although dopamine agonists do delay motor complications, they
are not without side effects. Trials have consistently shown higher rates of adverse
drug reactions in patients initially started on dopamine agonists.
randomized trial found that 28% of patients discontinued initial therapy with
dopamine agonists due to side effects versus only 2% of patients initially given
28 Regardless of initial therapy chosen, due to disease progression,
levodopa therapy will eventually be required, motor complications will develop, and
MAO-B inhibitors are an alternative method of enriching dopamine supply in early
disease. These agents increase nigrostriatal dopamine supply via the irreversible
inhibition of MAO-B, a major enzymatic pathway responsible for the metabolism of
dopamine in the brain, and require the presence of dopamine for clinical effect.
Though MAO-B inhibitors have been shown to delay the need for dopaminergic
therapy with levodopa, definitive efficacy comparisons are lacking.
Early guidance from the AAN supported either dopamine agonists or levodopa as
initial therapy for PD; more recent NICE and EFNS MDS-ES guidelines additionally
support the use of MAO-B inhibitors in initial therapy.
effectiveness of dopamine agonists and MAO-B inhibitors compared with levodopa
as initial treatment for PD (PD MED) trial set out to compare and contrast levodopa
versus levodopa-sparing therapies.
28 Patients assigned to monotherapy with MAO-B
inhibitors or dopamine agonists were generally younger and healthier than those
assigned levodopa as initial therapy. At 7-year follow-up, 72% of patients initially
assigned to MAO-B inhibitors withdrew from initial therapy and changed treatment
compared to 50% in the dopamine agonist group and 7% in the levodopa group
(P<0.0001). Among those patients initiated on MOA-B inhibitors, 48% withdrew
due to side effects and 36% withdrew due to lack of efficacy, and for patients
initiated on dopamine agonists, 82% withdrew due to side effects and 16% withdrew
28 As shown in prior studies, levodopa improved function and
quality of life to a greater degree; however, the primary mobility outcome did not
reach the prespecified minimally important difference. Mobility scores were not
significantly different between MAO-B inhibitors and dopamine agonists indicating
that MAO-B inhibitors are at least as effective as dopamine agonists in early therapy
28 Additionally, at 7 years, patients on dopamine agonists were on the highest
overall amount of medication. The study confirms that initial treatment with a
dopamine agonist, MAO-B inhibitor, or levodopa may all be reasonable approaches.
Disease severity, degree of functional impairment, life expectancy, and age guide
therapeutic drug selection in early PD. In younger patients (e.g., age <65 years) with
milder disease, such as L.M., the initiation of levodopa-sparing therapy with either a
dopamine agonist or MAO-B inhibitor would be appropriate. Initiating levodopa
therapy later in the course of PD delays the development of motor complications,
particularly the troubling peak-dose, levodopa-induced dyskinesias, which
eventually develop with advancing PD. Patients with younger age at disease onset,
such as L.M., may be at an increased lifetime risk of developing dyskinesias.
Although the PD MED trial did conclude that MAO-B inhibitors are at least as
effective as dopamine agonists for initial therapy, other meta-analyses show that the
degree of symptomatic benefit over placebo is small in comparison with those of
dopamine agonists over placebo.
30 Overall, there is a lack of comparative data
between MAO-B inhibitors and dopamine agonists. Therefore, use of MAO-B
inhibitors in initial therapy is often limited to young patients with more mild
functional impairments. In older patients (e.g., age >65 years), those with more
significant functional impairments, or those with limited life expectancy, use of
levodopa may be warranted, as a result of the large number of symptomatic benefits
associated with its use despite the relatively high risk of motor complications and
side effects. Additionally, levodopa may be more appropriate initial treatment in
older patients, because they may be more likely to experience intolerable CNS side
effects from dopamine agonists and less likely to develop motor complications over
In the case of L.M., his relatively young age, mild disease, and moderate functional
impairments make him a good candidate for initial therapy with a dopamine agonist.
L.M. will require levodopa therapy at a later time, when he reaches more advanced
stages of the disease. By initiating therapy first with a dopamine agonist, rescue
levodopa therapy can likely be started at smaller doses, and the onset of motor
complications that often occur with escalating doses and extended therapy with
CASE 59-1, QUESTION 5: L.M. is to be started on a dopamine agonist. Which agent should be selected?
Pharmacologic and Pharmacokinetic Properties of Dopamine Agonists
Bromocriptine Pramipexole Ropinirole Apomorphine Rotigotine
Ergot derivative Nonergoline Nonergoline Nonergoline Nonergoline
Bioavailability 7% (first-pass
(minutes) 70–100 60–180 90 10–60 15–18 (hours);
Protein binding 90%–96% 15% 10%–40% >99.9% 89.5%
Elimination route Hepatic Renal, 90%
Half-life (hours) 2–8 8–12 6 0.5–1 3–7
5-HT, serotonin; NA, not applicable.
Two generations of dopamine agonists have been used for the treatment of
idiopathic PD, in early-stage PD as monotherapy, or as an adjunct to levodopa in
patients with advanced disease. The comparative pharmacologic and
bromocriptine, pergolide, and cabergoline. These older agents are now rarely used
because of increased risk of retroperitoneal, pleural, and pericardial f ibrosis, as
well as a two- to fourfold increased risk for cardiac valve f ibrosis when compared
with nonergoline dopamine agonists and controls.
withdrawn in the United States (US) in 2007 for this reason, and although
cabergoline continues to be used in Europe, it is only indicated in the United States
for the treatment of hyperprolactinemia. Pramipexole, ropinirole, apomorphine, and
rotigotine are second-generation nonergoline dopamine agonists. Of these agents,
pramipexole and ropinirole are commonly prescribed. Apomorphine is available
only in injectable form, for use as a rescue agent in the treatment of hypomobility
“off” episodes in patients with PD. Rotigotine, a once-daily transdermal formulation,
was recently re-introduced to the market.
Dopamine agonists work by directly stimulating postsynaptic dopamine receptors
within the striatum. The two families of dopamine receptors are D1 and D2
like receptor family includes the D1 and D5 dopamine subtype receptors and the D2
like receptor family includes D2
, and D4 dopamine subtype receptors. Stimulation
receptors is largely responsible for reducing rigidity and bradykinesia,
whereas the precise role of the D1
ropinirole exhibit selectivity for D2
receptors without any significant affinity for D1
receptors whereas rotigotine has activity at all dopamine receptors.
dopamine agonists differ slightly from each other in terms of their affinities for
dopamine receptor subtypes, these agents produce similar clinical effects when used
to treat PD, and no compelling evidence favors one agent over another strictly on
efficacy measures. Instead, experience with the nonergoline dopamine agonists,
specifically pramipexole and ropinirole, makes them currently preferred as initial
dopamine agonists. Thus, either agent would be acceptable as initial therapy in L.M.
in the initial treatment of PD? How does ropinirole compare?
Pramipexole has been well studied as monotherapy in patients with early-stage PD
and as an adjunct to levodopa therapy in advanced-stage disease.
were multicenter, placebo-controlled, parallel-group studies, and parts of the Unified
Parkinson’s Disease Rating Scale (UPDRS) were used as the primary outcome
measures, specifically improvement in ADLs (Part II) and motor function scores
(Part III). Each evaluation on the UPDRS is rated on a scale of 0 (normal) to 4 (can
barely perform). Lower scores on the UPDRS after treatment indicate an
improvement in overall performance.
To view the UPDRS and other assessment tools for the symptoms of Parkinson’s disease, please visit
http://www.movementdisorders.org/MDS/Education/Rating-Scales.htm.
with early-stage PD (mean disease duration of 2 years).
patients were randomly assigned to receive one of four fixed doses (1.5, 3, 4.5, or 6
35 The pramipexole-treated patients had a 20% reduction in their
total UPDRS scores compared with baseline values, whereas no significant
improvement was observed in the placebo-treated patients. A trend toward
decreased tolerability was noted because the pramipexole dosage was escalated,
especially in the 6 mg/day group. A second study of 335 patients titrated doses up to
the maximal tolerated dose (not to exceed 4.5 mg/day) and then followed patients for
36 The mean pramipexole maintenance dosage was 3.8
mg/day. Those treated with pramipexole experienced significant improvements in
both the ADL scores (22%–29%; P<0.0001) and motor scores (25%–31%;
P<0.0001), whereas there were no significant changes in the placebo group.
Similar to pramipexole, ropinirole is a synthetic nonergoline dopamine agonist.
Although the drug is pharmacologically similar to pramipexole, it has some distinct
pharmacokinetic properties (Table 59-3). Unlike pramipexole, which is primarily
eliminated by renal excretion, ropinirole is hepatically metabolized and undergoes
significant first-pass hepatic metabolism.
pramipexole, ropinirole is approved for use as monotherapy in early-stage idiopathic
PD and as an adjunct to levodopa therapy in patients with advanced-stage disease.
Ropinirole has not been directly compared with pramipexole in randomized,
double-blind comparisons, but it appears to have comparable efficacy in indirect
comparison. In several randomized, double-blind, multicenter, parallel-group studies
comparing ropinirole with placebo, bromocriptine, or levodopa, 6 months of
monotherapy with ropinirole in patients with early PD significantly improves
UPDRS motor scores by approximately 20% to 30% compared with baseline
Rotigotine is a nonergoline dopamine receptor agonist that is formulated in a
transdermal patch delivery system designed for once-a-day application. It was
voluntarily withdrawn from the U.S. market in 2008 because of problems with crystal
formation in the patches; however, the patch was reformulated and re-approved by
the Food and Drug Administration (FDA) in April 2012. The original and
reformulated patches have demonstrated efficacy as monotherapy in early-stage
41–44 whereas only the original formulation has demonstrated efficacy as
adjunctive therapy to levodopa in patients with advanced stages of PD.
however, used in both situations.
A randomized, controlled trial conducted in Japanese patients with early-stage PD
found that the mean improvement in UPDRS Part II and III sum scores was 8.4 in the
rotigotine-treated group versus 4.1 in the placebo group (P = 0.002; 95% CI, –7.0 to
47 The average dose of rotigotine was 12.8 mg/24 hours in this study which
exceeds the highest recommended dose for early PD (6 mg/24 hours). Despite clear
benefits in improving ADLs and motor function, there is insufficient evidence at this
time to support that rotigotine prevents or delays motor fluctuations or dyskinesias.
The transdermal delivery may have several advantages over traditional oral
preparations including possible increase in adherence, ease of use in patients with
swallowing difficulty, and a more continuous stimulation of dopamine receptors. In
theory, these benefits may translate into improved efficacy. In randomized, controlled
trials comparing rotigotine to ropinirole as monotherapy or pramipexole as adjunct
therapy, rotigotine has been found to be noninferior when typical clinical doses are
CASE 59-1, QUESTION 7: How are pramipexole and ropinirole dosed? What is the appropriate dose of
Dopamine agonists should always be initiated at a low dosage and gradually
titrated to the maximal effective dose, as tolerated. This approach minimizes adverse
effects that may result in nonadherence or discontinuation of the drug. In clinical
trials, the maximal effective doses are variable and correlate with disease severity
and tolerability. Studies have found no difference in efficacy or safety measures
between immediate and long-acting formulations of dopamine agonists.
49 One fixeddose study of pramipexole in early PD showed that most patients responded
maximally at a dosage of 0.5 mg 3 times daily, although it has been shown to be
effective and well tolerated in doses as high as 4.5 mg/day (divided).
L.M. has normal renal function; therefore, immediate-release pramipexole should
be started at an initial dosage of 0.125 mg 3 times daily for 5 to 7 days. His dosage
may be increased weekly by 0.125 to 0.25 mg/dose as tolerated and up to the
maximal effective dose, not to exceed the maximum dose of 4.5 mg/day.
with a creatinine clearance of less than 50 mL/minute should be dosed less frequently
than those with normal renal function.
34 Patients with a creatinine clearance of 30 to
50 mL/minute should receive a starting dose of 0.125 mg twice daily up to a maximal
dose of 0.75 mg 3 times daily; patients with a creatinine clearance of 15 to 30
mL/minute should receive a starting dose of 0.125 mg daily up to a maximal dose of
1.5 mg daily. Pramipexole has not been studied in patients with a creatinine
clearance of less than 15 mL/minute or those receiving hemodialysis. A once-daily
extended-release formulation of pramipexole is also available; patients can be
switched overnight from immediate-release pramipexole at the same daily dose. The
use of the extended-release formulation is not recommended for patients with a
creatinine clearance less than 30 mL/minute or for those receiving hemodialysis.
Ropinirole should be initiated at a dosage of 0.25 mg 3 times daily with gradual
titration to clinical response in weekly increments of 0.25 mg/dose over the course of
4 to 6 weeks, not to exceed 24 mg/day.
37 Patients wishing to take the drug less
frequently can be switched directly to an extended-release once-daily formulation,
with renal dysfunction and can be used in doses up to 18 mg/day in patients on
Transdermal rotigotine is available in several patch strengths (Table 59-2). For
patients with early-stage PD, it is recommended to start rotigotine at 2 mg/24 hours
with dose increases of 2 mg/24 hours no sooner than weekly based on clinical
50 The maximum recommended dose in early PD is 6 mg/24
hours whereas 8 mg/24 hours is recommended in advanced PD. Clinical trials have
often used doses up to 16 mg/24 hours.
51 The time to reach steady state plasma
concentrations of rotigotine is approximately 2 to 3 days after initial patch
50 A multinational, open-label study demonstrated that patients with
advanced PD taking pramipexole <2 mg/day or ropinirole <9 mg/day can be safely
switched directly to rotigotine with no cross-titration.
52 Rotigotine is metabolized via
conjugation and N-dealkylation, and the inactive conjugates are excreted in the urine.
No adjustments are required for patients with hepatic or renal insufficiency.
CASE 59-1, QUESTION 8: What are the adverse effects of pramipexole and ropinirole? How can these be
Because pramipexole, ropinirole, and rotigotine are all approved for use as
monotherapy in early-stage disease and as adjunctive therapy in advanced-stage
disease, the adverse events of these agents have been evaluated as a function of
disease stage. In studies of patients with early-stage disease, the most common side
effects were nausea (28%–47%), application site reactions (39%, rotigotine only),
dizziness (25%–40%), somnolence (22%–40%), insomnia (17%–19%), constipation
(14%), asthenia (14%), hallucinations (9%), and leg edema (5%).
Administration with food may help to relieve nausea and/or vomiting. With continued
use, many patients exhibit tolerance to the gastrointestinal side effects. CNS side
effects were the most common reason for discontinuation of these agents with older
patients particularly susceptible to hallucinations and other CNS side effects. The
incidence of orthostatic hypotension was relatively low (1%–9%) and may in part
reflect the exclusion of patients with underlying cardiovascular disease in several of
In advanced-stage disease, the most common adverse events of dopamine agonists
were orthostatic hypotension (10%–54%), dyskinesias (26%–47%), application site
rotigotine only, dose related), nausea (25%), insomnia (27%), hallucinations
(11%–17%), somnolence (11%), and confusion (10%).
reasons for discontinuing these agents are mental disturbances (e.g., nightmares,
confusion, hallucinations, insomnia) and orthostatic hypotension. Dyskinesias that are
experienced when dopamine agonists are used in combination with levodopa in
advanced-stage disease may require lowering the dose of levodopa or, in some
Sudden, excessive daytime somnolence, including while driving, has been
reported with dopamine agonists and has resulted in accidents.
patients did not always report warning signs before falling asleep and believed they
were alert immediately before the event. Labeling for these drugs includes a warning
that patients should be alerted to the possibility of falling asleep while engaged in
daily activities. Patients should be advised to refrain from driving or other
potentially dangerous activities until they have gained sufficient experience with the
dopamine agonist to determine whether it will hinder their mental and motor
performance. Caution should be advised when patients are taking other sedating
medications or alcohol in combination with dopamine agonists. If excessive daytime
somnolence does occur, patients should be advised to contact their healthcare
Dopamine agonist therapy in patients with PD is associated with 2- to 3.5-fold
increased odds of developing an impulse control disorder.
similar for both pramipexole and ropinirole whereas it is less clear with rotigotine.
In one study, a prevalence of 6.1% was noted for pathologic gambling in patients
with PD compared with 0.25% for age- and sex-matched controls.
represent variations of a behavioral syndrome termed dopamine dysregulation
57 Other features of the syndrome have been reported, including punding
(carrying out repetitive, purposeless motor acts), hypersexuality, walkabout (having
the urge to walk great distances during on-times, often with no purpose or destination
and abnormalities in time perception), compulsive buying, binge eating, drug
hoarding, and social independence or isolation.
57 The syndrome appears to be more
common among younger, male patients with early-onset PD, as well as those having
novelty-seeking personality traits, depressive symptoms, and current use of alcohol
58 Management of impulse control disorders can be challenging,
because it often requires modification of dopaminergic therapies, which must be
carefully balanced with the accompanying risk of worsening motor function.
Underlying depression, if present, should be treated and may improve impulse
control. Nonpharmacologic measures (such as limiting access to money or the
Internet) may be helpful; in some cases, antipsychotic drugs may be considered, but
must also be used carefully to avoid precipitating motor disability.
Although L.M. is younger than 65 years of age, he may be at increased risk for
visual hallucinations and cognitive problems from dopamine agonist therapy. He
should be monitored closely for occurrence or exacerbation of these side effects. He
should also be evaluated for lightheadedness before initiation of pramipexole and
counseled to report dizziness or unsteadiness, because this may lead to falls. He
should be reassured that if these effects are caused by pramipexole, they should
subside with time and that he should not drive or operate complex machinery until he
can assess the effect of the drug on his mental status. L.M. should be counseled about
the possibility of excessive, and potentially unpredictable, daytime somnolence
because pramipexole is introduced. L.M. does not appear to have a problem with
excessive alcohol use; however, he and his family should be educated about his
increased risk for impulse control disorders and advised to report any new, unusual,
or uncharacteristic behaviors or increased use of alcohol.
MONOAMINE OXIDASE-B INHIBITORS
The monoamine oxidase-B inhibitors are irreversible inhibitors of MAO-B, a major
enzymatic pathway responsible for the metabolism of dopamine in the brain, and
inhibition increases the amount of striatal dopamine.
60 The discovery that ingestion of
MPTP causes rapid and irreversible parkinsonism led to the finding that the
neurotoxicity associated with MPTP is not directly caused by MPTP itself, but rather
the oxidized product, L-methyl-4-phenylpyridinium (MPP).
is a two-step process mediated in part by MAO-B. Inhibition of MAO-B can inhibit
the oxidative conversion of dopamine to potentially reactive peroxides. This finding
has led investigators to study whether inhibition of this enzyme is neuroprotective.
In animals, pretreatment with selegiline (also referred to as deprenyl) protects
against neuronal damage after the administration of MPTP.
Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) study was
designed to test the hypothesis that the combined use of selegiline and an antioxidant
(α-tocopherol) early in the course of the disease may slow disease progression.
primary outcome was the length of time that patients could be sustained without
levodopa therapy (an indication of disease progression). Early treatment with
selegiline 10 mg/day delayed the need to start levodopa therapy by approximately 9
months compared with patients given placebo; however, long-term observation
showed that the benefits of selegiline were not sustained and diminished with time. In
an extension of the study, patients originally assigned to selegiline tended to reach the
endpoint of disability after 1 year of observation even more quickly than did those
not assigned to receive selegiline.
Initial selegiline treatment did not alter the
development of levodopa adverse effects such as dyskinesias and wearing-off and
Although selegiline did not prove to be neuroprotective, the finding that MAO-B
inhibitors can delay the need for dopaminergic therapy by at least several months is
clinically relevant and is supported by several randomized, controlled trials.
Aside from the DATATOP trial, studies of selegiline are limited by relatively small
sample sizes. As a result, a large meta-analysis of MAO-B inhibitors in early PD
30 When analyzed for selegiline, the levodopa dose necessary to
control symptoms was 67 mg (14–119 mg; P = 0.01) lower in the selegiline arm.
This analysis found that the total, motor, and ADL scores of the UPDRS were
significantly improved in the selegiline arm at 3 months. A subsequent Cochrane
Review found that the selegiline-treated arms scored 3.79 points better (95% CI:
2.21, 5.3) when looking at the weighted mean difference in motor UPDRS score.
Although oral selegiline continues to be FDA-approved only as adjunct treatment to
carbidopa/levodopa, the evidence suggests efficacy in monotherapy, and it is used as
Rasagiline is a second-generation, irreversible selective inhibitor of MAO-B that is
FDA-approved as both monotherapy and adjunct therapy in PD. Rasagiline is
otherwise differentiated from selegiline primarily in that it is a more potent inhibitor
of MAO-B and does not carry the same potential for adverse effects resulting from
Rasagiline was studied as monotherapy in early PD in a randomized, double-blind,
placebo-controlled trial comparing rasagiline 1 or 2 mg daily with placebo (n =
66 After 6 months of therapy, the mean adjusted change in UPDRS scores
compared with placebo was improved in both the 1- and 2-mg groups (P<0.001).
These changes are quantitatively similar to those
observed with levodopa therapy. This study used a delayed-start design, wherein
at the end of the initial 6 months of treatment, patients who received placebo were
found that patients receiving rasagiline for all 12 months had less functional decline
than patients in whom rasagiline was delayed.
67 The mean adjusted difference in total
UPDRS scores at 12 months for patients receiving rasagiline 2 mg/day for all 12
months was –2.29 compared with the delayed-start rasagiline 2-mg group (P = 0.01).
As a result, rasagiline was FDA-approved for use as monotherapy in early PD.
These encouraging findings also suggested that neuroprotection might be afforded by
rasagiline and prompted a larger, more definitive study.
The Attenuation of Disease Progression with Azilect Given Once-daily
randomly assigned to receive rasagiline or placebo for 36 weeks, at which time
rasagiline-treated subjects continued therapy, and the placebo group was switched to
rasagiline; all patients were then followed for an additional 36 weeks. To prove
disease modification attributable to rasagiline with either dose, the early-start
treatment group had to meet each of three hierarchic endpoints, based on magnitude
and rate of change of UPDRS scores during different periods of the study. At the end
of the study, rasagiline failed to meet all of the prespecified endpoints and the authors
were unable to confirm any disease-modifying effects.
No direct comparisons of rasagiline and selegiline are available. Existing data
were compared in an industry-sponsored, indirect meta-analysis, which found a
significant advantage for rasagiline monotherapy on UPDRS scores.
risk for discontinuation and adverse events favored rasagiline. Rasagiline is
primarily metabolized via cytochrome P450 (CYP) 1A2 and N-dealkylation,
whereas selegiline is metabolized via CYP2B6, CYP2C9, and CYP3A4/5 to
amphetamine-like metabolites (L-methamphetamine and L-amphetamine). As a result
of their MAO-B inhibition, similar precautions regarding drug interactions exist;
caution should be taken when using MAO-B inhibitors with proserotonergic agents
such as antidepressants, triptans, and linezolid due to the risk of serotonin syndrome.
Although tyramine-challenge studies have not demonstrated any clinically significant
reactions with these MAO-B inhibitors, the product labeling still contains a warning
that patients should be advised to restrict tyramine intake.
Selegiline is available in a 5-mg capsule or tablet and as a 1.25-mg orally
disintegrating tablet. It is also available in a transdermal patch, but this formulation is
not approved for use in PD (approved for treatment of major depressive disorder).
The bioavailability of conventional selegiline is low, and it undergoes extensive
hepatic first-pass metabolism into amphetamine-based metabolites, which may
contribute to neurologic side effects.
60 The usual dosage of conventional selegiline is
10 mg/day administered as 5 mg in the morning and early afternoon. It is not given in
disintegrating tablet formulation dissolves in the mouth in contact with saliva and
undergoes pregastric absorption. This formulation minimizes the effect of first-pass
metabolism in comparison with conventional selegiline, resulting in higher plasma
concentrations and reductions in the amphetamine-based metabolites.
should be used with caution in patients with severe hepatic impairment or with
creatinine clearance less than 30 mL/minute.
Rasagiline is available in 0.5- and 1-mg tablets. When used as monotherapy, it is
initiated at 1 mg daily. When combined with levodopa, the initial dose is lowered to
0.5 mg daily and can be increased to 1 mg daily based on response. In patients with
mild hepatic impairment, the dose should be reduced to 0.5 mg daily, but use should
be avoided in those with moderate-to-severe hepatic impairment. Additionally,
because rasagiline lacks the amphetamine-like metabolites of selegiline, it also lacks
the time-specific dosing constraints.
The most common adverse effects of both agents include nausea (6%–20%),
dizziness (11%–14%), headache (4%–14%), and dry mouth (4%–6%).
effects such as hallucinations, vivid dreams, and confusion also occur but at a lower
rate as compared with dopamine agonists. Although the oral disintegrating tablet
reduces the amphetamine-based metabolites, there are higher rates of reported side
effects, likely as a result of the higher plasma concentration of selegiline.
meta-analysis of MAO-B inhibitors in early PD found a higher incidence of reported
side effects among the MAO-B inhibitor (all but one study used selegiline) versus
non-MAO-B inhibitor groups (OR: 1.36, 1.02–1.8, P = 0.04).
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