CASE 59-1, QUESTION 9: L.M. has responded well to pramipexole 1 mg 3 times daily for the past 18
Dopamine itself does not cross the blood–brain barrier. Levodopa, a dopamine
precursor with no known pharmacologic action of its own, crosses the blood–brain
barrier, where it is converted by the enzyme aromatic amino acid (dopa)
decarboxylase to dopamine. Levodopa has been a mainstay of PD treatment since the
1960s. Nearly all patients will eventually require treatment with the drug, regardless
Because significant amounts of levodopa are peripherally (extracerebrally)
metabolized to dopamine by dopa decarboxylase, extremely high doses are necessary
if administered alone. For this reason, levodopa is always coadministered with a
dopa decarboxylase inhibitor. This allows the dose of levodopa to be decreased by
73 By combining levodopa with a dopa decarboxylase inhibitor that does not
penetrate the blood–brain barrier, a decrease in the peripheral conversion of
levodopa to dopamine can be achieved, whereas the desired conversion within the
striatum remains unaffected. This combination also shortens the time needed to
achieve optimal effects by several weeks, because the dopa decarboxylase inhibitor
substantially decreases dose-limiting levodopa-induced nausea and vomiting. The
two peripheral decarboxylase inhibitors in clinical use are benserazide (unavailable
in the US) and carbidopa. A fixed combination of carbidopa and levodopa is
available in ratios of 1:4 (carbidopa/levodopa 25/100) and 1:10
(carbidopa/levodopa 10/100 and 25/250). Carbidopa/levodopa is also available as
an immediate-release, orally disintegrating tablet and extended-release capsule, both
of which may be used in early PD. In addition, controlled-release, extended-release,
formulations are available and are discussed for management of motor
The optimal time to initiate levodopa therapy must be individualized because
chronic levodopa use is associated with the development of motor complications and
dyskinesias. These observations led to the understanding that chronic levodopa
therapy may actually accelerate the neurodegenerative process through formation of
free radicals generated by dopamine metabolism.
Levodopa Therapy in Parkinson’s Disease (ELLDOPA) study was designed to
determine whether long-term use of levodopa accelerates neurodegeneration and
74 After 42 weeks, the severity of symptoms as measured
by changes in the total UPDRS score increased more in the placebo group than in all
of the groups receiving levodopa. This validated that levodopa use does not result in
accelerated progression of the disease based on clinical evaluations. In untreated
individuals, there is little reason to start levodopa until the patient reports worsening
of function (socially, vocationally, or otherwise). The need for levodopa therapy may
be delayed by initiating therapy first with a dopamine agonist or MAO-B inhibitor.
This approach is particularly advantageous in younger patients who will likely live
many years with PD and have a high lifetime risk for developing motor
complications. In the case of L.M., he is now experiencing bothersome symptoms
despite near-maximal dopamine agonist therapy, and it has progressed sufficiently to
threaten his job performance. Although the dose of pramipexole could be increased,
he may experience more daytime somnolence; thus, levodopa should be added to his
CASE 59-1, QUESTION 10: The decision is made to begin L.M. on carbidopa/levodopa. How should it be
About 70 to 100 mg/day of carbidopa is necessary to saturate peripheral dopa
It is usually unnecessary and more costly to administer carbidopa in
higher amounts. Therapy should be initiated with immediate-release
carbidopa/levodopa 25 mg/100 mg 3 times a day. The immediate-release formulation
is preferred because it allows for much easier dose adjustment. In the case of L.M.,
the dose can then be increased by 100 mg of levodopa every day or every other day
up to eight tablets (800 mg) or to the maximal effective dose, to individual
requirements, or as tolerated.
Troublesome peak-dose dyskinesias may occur as a result of high levels of
dopaminergic drug activity. If these occur, the dose or frequency may be adjusted,
while giving consideration to balancing the most useful dose (e.g., maximizing the
patient’s on-time) with that which does not produce unacceptable side effects (e.g.,
troublesome dyskinesias). Because L.M. is currently being treated with a dopamine
agonist, he must be monitored closely for the development of motor complications
with the addition of levodopa.
Most patients with early PD will begin therapy on levodopa 300 mg/day and will
demonstrate response before reaching 1,000 mg/day.
exceed 750 mg/day, patients such as L.M. can be switched from the 1:4 ratio of
carbidopa/levodopa to the 1:10 ratio to prevent providing excessive amounts of
decarboxylase inhibitor. For example, if L.M. needed 800 mg/day of levodopa, two
carbidopa/levodopa 10/100 tablets 4 times daily could be administered. If L.M. had
not been initially treated with a dopamine agonist, some clinicians would consider
adding a dopamine agonist after the daily levodopa dose has been increased to more
than 600 mg because dopamine agonists directly stimulate dopamine receptors, have
longer half-lives, and result in a lower incidence of dyskinesias, thus providing a
smoother dopaminergic response.
Clinical response to levodopa therapy may be altered by modifying dietary amino
73 Levodopa is actively transported across the blood–brain barrier by
a large neutral amino acid transport system. This transport system also facilitates the
blood-to-brain transport of amino acids such as L-leucine, L-isoleucine, L-valine, and
L-phenylalanine. Levodopa and these neutral amino acids compete for transport
mechanisms, and high plasma concentrations of these amino acids can decrease brain
75 Patients should be instructed to take immediate-release
carbidopa/levodopa 30 minutes before or 60 minutes after meals for optimal
times. To what extent is levodopa contributing to these problems? How should they be managed?
Although levodopa is the most effective agent for PD, it is associated with many
undesirable side effects, such as nausea, vomiting, and anorexia (50% of patients);
postural hypotension (30% of patients); and cardiac arrhythmias (10% of patients).
In addition, mental disturbances are encountered in 15% of patients, and abnormal
involuntary movements (dyskinesias) can be seen in up to 55% of patients during the
first 6 months of levodopa treatment.
Although more commonly encountered with dopamine agonists, psychiatric side
effects are also associated with levodopa therapy and include confusion, depression,
psychosis, hypomania, and vivid dreams.
73 Those with underlying or preexisting
psychiatric disorders and those receiving high doses of levodopa for prolonged
77 Concurrent anticholinergics or amantadine therapy can
exacerbate these symptoms. Advancement of the PD itself correlates with cognitive
decline and greater frequency of CNS findings, possibly mediated through an
underlying Lewy body pathology.
In some situations, it may be difficult to separate
the respective drug from disease effects.
Some patients receiving levodopa experience psychomotor excitation (e.g.,
overactivity, restlessness, agitation). Similarly, hypomania has been reported in up to
8% of patients and is characterized by grandiose thinking, flight of ideas, tangential
thinking, and poor social judgment. Normal sexual activity often is restored with
improved motor function; however, hypersexuality and libido are increased in about
1% of levodopa-treated patients.
In general, most of the mental disturbances are dose-related and can be lessened
by reducing the dose of the dopaminergic agent. In patients such as L.M. who are
concurrently receiving levodopa and a dopamine agonist, the dose reduction should
be attempted first with the dopamine agonist. If symptoms do not improve, a
reduction in the dose of levodopa may also be warranted. These dose reductions
may, however, be impractical for L.M. because a return of parkinsonian symptoms is
likely, and the benefits of levodopa therapy may outweigh the risk for mental
CASE 59-1, QUESTION 12: What role do anticholinergic drugs play in the treatment of PD? Should L.M.
receive an anticholinergic agent?
Anticholinergic drugs have been used to treat PD since the mid-1800s, when it
was discovered that symptoms were reduced by the belladonna derivative hyoscine
they are used to specifically target tremor. Although tremor may improve with
dopaminergic drugs via the restoration of balance between dopamine and
acetylcholine, resolution of tremor may be incomplete. Anticholinergic drugs such as
benztropine and trihexyphenidyl work by blocking the excitatory neurotransmitter
acetylcholine in the striatum, which minimizes the effect of the relative increase in
cholinergic sensitivity. Until the late 1960s, when amantadine and levodopa were
introduced, anticholinergics were a mainstay of treatment; however, because of their
undesirable side effect profile and poor efficacy relative to levodopa in treating
bradykinesia and rigidity, anticholinergic agents are no longer used as first-line
agents. These drugs produce both peripherally and centrally mediated adverse
effects. Peripheral effects, such as dry mouth, blurred vision, constipation, and
urinary retention, are common and bothersome.
20 Anticholinergic agents can increase
intraocular pressure and should be avoided in patients with angle-closure glaucoma.
CNS effects can include confusion, impairment of recent memory, hallucinations, and
20 Patients with PD are often more susceptible to these central effects
because of advanced age, intercurrent illnesses, and impaired cognition.
Anticholinergics are usually reserved for the treatment of resting tremor early in the
disease, particularly in younger patients with preserved cognitive function. Given his
history and clinical presentation and based on the absence of tremor, L.M. would not
be an appropriate candidate for an anticholinergic drug.
Treatment through the Progression of Parkinson’s
LEVODOPA AND ADJUNCTIVE THERAPY
The chronic, progressive nature of PD predicts that patients will develop worsening
of motor control through the later stages of the disease; thus, enhanced motor control
through the use of levodopa, in conjunction with symptomatic adjunctive agents, will
be necessary. Agent selection is guided by efficacy for motor symptom control,
adverse effects, and motor complication risk. Agents indicated by the AAN,
17 guidelines for symptomatic adjunct therapy and
management of motor complications in late PD are outlined in Figure 59-3.
CASE 59-1, QUESTION 13: L.M. had a dramatic improvement in all of his parkinsonian symptoms with the
After 6 months of treatment, he began to experience dyskinesias occurring 1 to 2
hours after a dose. They manifested as facial grimacing, lip smacking, tongue
protrusion, and rocking of the trunk. Decreasing his pramipexole dose to 0.5 mg 3
times daily and gradually decreasing his dosage of carbidopa/levodopa to 25 mg/250
mg 3 times daily lessened the symptoms. After 3 years of levodopa therapy, more
serious problems have begun to emerge. In the mornings, L.M. often experiences
immobility. Nearly every day, he has periods (lasting for a few minutes) in which he
cannot move, followed by a sudden switch to a fluid-like state, often associated with
dyskinetic activity. He continues to take carbidopa/levodopa 3 times daily, but gains
symptomatic relief for only 3 to 4 hours after a dose. Also, the response to a given
dose varies and is often less in the afternoon. At times, he becomes “frozen,”
particularly when he needs to board an elevator or is required to move quickly. What
are possible explanations for these alterations in clinical response?
Though variable, the initial levodopa response period may last up to 5 years. After
this initial period of stability, 50% to 90% of patients receiving levodopa for 5 or
more years will eventually experience motor complications.
may present as periods of either too much (dyskinetic) dopaminergic activity, too
little (akinetic) dopaminergic activity, or in combination.
In evaluating these motor fluctuations, it is important to ascertain which effects are
attributable to the disease and which are attributable to the drug. For example,
levodopa-induced peak-dose dyskinesias often appear concurrently with the
development of motor fluctuations.
79 Peak-dose choreiform dyskinesias, brief,
irregular and jerky movements, are the most common form of dyskinesias that occur
with chronic levodopa (and sometimes dopamine agonist) therapy. These symptoms
frequently subside at the end of the dosing interval because levodopa levels fall.
Their severity is related to levodopa dose, disease duration and stage, and younger
If peak-dose dyskinesias occur, the following strategies should be
considered: The levodopa dose can be lowered but given more frequently;
consideration can be given to switching patients to immediate-release tablets if
taking modified-release formulations of carbidopa/levodopa (for ease in refining
dose adjustments); agents that prolong the half-life of levodopa but do not provide
stable levodopa plasma concentrations (e.g., COMT inhibitor, MAO-B inhibitor) can
be added; or an antidyskinetic agent such as amantadine can be used. Variations in
the rate and extent of levodopa absorption, dietary substrates (e.g., large neutral
amino acids) that compete with cerebral transport mechanisms, levodopa drug–drug
interactions (Table 59-4), and competition for receptor binding by levodopa
metabolites can further explain the variable responses observed to levodopa.
Figure 59-3 Levodopa metabolism in the human body. AADC, aromatic amino acid decarboxylase; COMT,
Two of the more common motor complications are the wearing-off effect and the
on–off effect. The wearing-off effect is most predictable, occurring in the latter part
of the dosing interval after a period of relief. Because levodopa is a short-acting
agent with an elimination half-life of about 1.5 hours, much of the effect from the
evening dose will dissipate by morning.
78 For this reason, it is not surprising that
L.M. is experiencing a period of immobility on arising. This is alleviated in most
patients shortly after taking the morning dose. Wearing off can be improved by
various means such as shortening the dosing interval or with the addition of
adjunctive therapy (if not already present) with a dopamine agonist, MAO-B
inhibitor or levodopa extender such as a COMT inhibitor. The on–off effect is
described as random fluctuations from mobility (often associated with dyskinesias)
to the parkinsonian state, which appear suddenly as if a switch has been turned on or
off. These fluctuations can last from minutes to hours and increase in frequency and
intensity with time. Despite accompanying dyskinesias, most patients prefer to be in
an on rather than an off (or akinetic) state; however, for some patients, dyskinesias
can be more disabling than parkinsonism.
Early in the course of disease, it is usually possible to control parkinsonian
symptoms without inducing dyskinesias via medication adjustments; however,
because the disease advances and the therapeutic window narrows, cycling between
on periods complicated by dyskinesia and off periods with resulting immobility is
79 Eventually, despite adjustments in levodopa dose, many patients with
advanced PD experience either mobility with severe dyskinesias or complete
immobility. In most patients, this effect has no clear relationship to the timing of the
dose or levodopa serum levels.
The pathophysiologic basis for motor complications and dyskinesias is not entirely
clear, but incomplete delivery of dopamine to central receptors is likely
78 Because the disease progresses and dopamine terminals are lost, the
capacity to store dopamine presynaptically is diminished, impairing the ability to
maintain relatively constant striatal dopamine concentrations.
dopamine receptors are subject to intermittent, pulsatile stimulation, rather than a
more physiologic tonic stimulation. Overactivity of excitatory pathways mediated by
neurotransmitters such as glutamate may also be involved.
CASE 59-1, QUESTION 14: What options are available to reduce the motor fluctuations experienced by
MODIFIED-RELEASE CARBIDOPA/LEVODOPA FORMULATIONS
A more sustained delivery of levodopa than that achieved with routine oral dosing
may theoretically reduce motor complications, by more effectively replicating normal
physiology. Three products designed to prolong carbidopa/levodopa delivery
include a controlled-release tablet, an extended-release capsule, and an enteral
suspension administered as a gastrointestinal infusion. The use of the enteral
suspension for gastrointestinal infusion has shown reductions in off-time of 1.91
hours (P = 0.0018) and an increase in on-time of 1.86 hours (P = 0.0059) in a 12-
week study of patients with severe motor fluctuations and hyper/dyskinesias.
result of its pump administration via a permanent duodenal/upper jejunal tube, this
method is typically reserved as last-line therapy for use in specialized centers.
Controlled-Release Carbidopa/Levodopa
A controlled-release (CR) tablet formulation of carbidopa/levodopa is available,
containing 25-mg carbidopa and 100-mg levodopa or 50-mg carbidopa and 200 mg
clinical study has generally not found a sustained difference in off-time, or a
reduction in dyskinesias, with the CR preparation compared with the immediaterelease preparation.
18 As a result, switching to CR carbidopa/levodopa as a
primary strategy to reduce off-time or lessen dyskinesias is not recommended.
A likely reason for the lack of superior effect with CR carbidopa/levodopa as
compared with the immediate-release formulation is its variable absorption.
Controlled-release carbidopa/levodopa is about 30% less bioavailable than the
immediate-release formulation. Patients converted from standard
carbidopa/levodopa to the CR formulation should receive a dose that will provide
10% more levodopa, and then the dose should be titrated upward to clinical
Interestingly, administration with food enhances levodopa peak by 25%.
Given that there is no obvious advantage to CR carbidopa/levodopa, L.M. should not
be switched to this formulation.
Extended-Release Carbidopa/Levodopa
The extended-release (ER) capsule formulation of carbidopa/levodopa contains a
combination of both immediate- and extended-release beads designed to circumvent
the pharmacokinetic concerns seen with the CR tablet formulation. Although both
formulations persist for up to 6 hours, the ER capsule provides a faster time to
symptom relief, with a peak that is comparable to the immediate-release formulation
(1 hour vs. up to 2 hours for CR).
82 Similar to CR, the ER formulation reduces
levodopa bioavailability by approximately 50%.
provides specific dose conversions from immediate-release preparations. Converse
to the CR preparation, high-fat and high-calorie food reduces levodopa peak and may
delay absorption by 2 to 3 hours, and it is recommended that the first dose of the day
be given 1 to 2 hours prior to eating. In patients with difficulty swallowing, these
capsules may be opened and sprinkled on applesauce, which is an additional
advantage to the CR formulation.
84 After being titrated to a stable dose during weeks 1 to 9, patients were
when compared to the IR formulation. This effect was accompanied by an increase in
on-time without troubling dyskinesia of approximately 1 hour (P = 0.0002). Notably,
of patients converted per manufacturer direction, 60% of patients required a further
dosage increase and 13% required a dosage decrease.
Drug Interaction Mechanism Comments
Anticholinergics ↓ Levodopa effect ↓ Gastric emptying,
Watch for ↓ levodopa effect when
anticholinergics cause ↓ GI motility. When
anticholinergic therapy is discontinued in a
↓ amount absorbed patient on levodopa, watch for signs of
levodopa toxicity. Theoretic interaction with
Ferrous sulfate ↓ Levodopa oral
Avoid concomitant administration or
separate administration by at least 2 hours
Food ↓ Levodopa effect Large, neutral amino
Although levodopa is usually taken with
meals to slow absorption and ↓ central
emetic effect, high-protein diets should be
Hypertensive crisis Peripheral dopamine
Avoid combination use; monoamine oxidase
type B (MAO-B) inhibitors such as
selegiline can be used, but the dose of
levodopa should be reduced after 2–3 days
of therapy; carbidopa might minimize
hypertensive reaction to levodopa in
Observe for response; may need to switch
Metoclopramide ↓ Levodopa effect Central dopamine
↓ Levodopa effect Central blockade of
Avoid combination use; important
Phenytoin ↓ Levodopa effect Mechanism
Not observed when levodopa given with
carbidopa; avoid levodopa monotherapy
with vitamin B6 supplementation
GI, gastrointestinal; MAOI, monoamine oxidase inhibitor.
Based upon this evidence, the ER formulation may improve off-time for L.M., but
is unlikely to impact his dyskinesias. Therefore, it may not be appropriate to switch
therapy. Taking his immediate-release carbidopa/levodopa more frequently while
avoiding substantial increases in the total daily dose, which could worsen his
dyskinesias, may improve his condition. Taking his morning dose before arising from
bed may help with his early-morning problems. If the symptoms that L.M. is
experiencing are not improved with these changes, a number of adjunctive agents
such as dopamine agonists, apomorphine rescue, amantadine, COMT inhibitors, and
MAO-B inhibitors can be considered.
The effectiveness of pramipexole added to levodopa therapy in advanced PD was
evaluated in a multicenter, placebo-controlled study of 360 patients with a mean
85 Pramipexole was titrated gradually to the maximal
effective dose as tolerated. At the end of a 6-month maintenance period, patients
treated with pramipexole had a 22% improvement in their ADLs (P<0.0001) and a
25% improvement in their motor scores (P<0.01) compared with baseline values.
Patients treated with pramipexole also had a 31% improvement in the mean off-time,
compared with a 7% improvement in the placebo-treated group (P<0.0006).
Dyskinesias and hallucinations were more common in pramipexole-treated patients
and necessitated levodopa dose reduction in 76% of patients compared with 54% in
the placebo group. The total daily levodopa dose was decreased by 27% in those
treated with pramipexole compared with 5% in the placebo group.
Ropinirole has been found to improve motor scores when added to levodopa
therapy in patients with advanced-stage disease.
In a multicenter, double-blind,
randomized parallel-group study, patients treated with ropinirole achieved a greater
reduction in percent of time spent off during waking hours when compared to placebo
(11.7% vs. 5.1%), which was a difference of 0.4 hours. A greater amount of
ropinirole-treated patients achieved a significant 20% reduction in time spent off
(35% vs. 13%, P = 0.003). In those treated with levodopa, the levodopa dose was
decreased by an average of 19%.
Long-acting dopamine agonist formulations, including ER ropinirole and
rotigotine, have also shown reductions in off-time. In a study of 208 PD patients not
optimally controlled with levodopa after up to 3 years of therapy with less than 600
mg/day of levodopa, a prolonged-release, once-daily formulation of ropinirole was
found to improve motor scores in a similar fashion to increase the levodopa dose;
however, only 3% of ropinirole-treated subjects experienced dyskinesias compared
with 17% of levodopa-treated patients (P<0.001).
treatment benefits were observed within 2 weeks of initiation.
ropinirole has been found to reduce off-time more than the immediate-release
preparation in advanced PD. A randomized, double-blind trial of 343 patients over
24 weeks found that compared to the immediate-release formulation, significantly
88 These results are confounded by
the relatively higher doses of ER ropinirole and greater reductions in levodopa
achieved by the ER formulation. Rotigotine has also been evaluated for reduction in
off-time in advanced PD patients and
has been shown to significantly reduce off-time by approximately 2.5 hours, with
benefits seen as early as the first week of therapy.
Because L.M. has advanced disease and is experiencing motor fluctuations despite
a treatment regimen that includes a dopamine agonist, further dose adjustments of the
dopamine agonist may provide little additional benefit. Any adjustments must be
made with consideration of worsening his dyskinesias and the possibility of
exacerbating CNS adverse effects.
Apomorphine is an injectable dopamine agonist that is approved as rescue therapy
for treatment of hypomobility or off episodes in patients with PD. In a randomized,
double-blind, parallel-group study of 29 patients, rescue treatment with apomorphine
resulted in a 34% reduction in off-time, approximately 2 hours, compared with 0% in
89 Mean UPDRS motor scores were reduced by 23.9
points (62%) in those treated with apomorphine, compared with 0.1 (1%) in those
receiving placebo (P<0.001). Adverse events in the apomorphine group included
yawning (40%), dyskinesias (35%), drowsiness or somnolence (35%), nausea or
vomiting (30%), and dizziness (20%), although only yawning was statistically
different from placebo (40% vs. 0%; P = 0.03).
Because nausea and vomiting frequently occur with apomorphine treatment, it
should be administered with an antiemetic such as trimethobenzamide. The antiemetic
should be started 3 days before initiating apomorphine and continued for the first 2
89 Apomorphine should not be used with ondansetron and other
serotonin antagonists used to treat nausea because the combination may cause severe
hypotension. In addition, other antiemetics, such as prochlorperazine and
metoclopramide, should not be given concurrently because these dopamine
antagonists may decrease the effectiveness of apomorphine.
Doses of apomorphine range from 2 to 6 mg per subcutaneous injection. A 2-mg
test dose is recommended while monitoring blood pressure. If tolerated, the
recommendation is to start with a dose of 2 mg and increase the dose by 1 mg every
few days if needed. Peak plasma levels are observed within 10 to 60 minutes after
someone else to inject the drug once hypomobility has occurred. In severe cases,
L.M. is experiencing motor fluctuations almost daily, long-term frequent
apomorphine use would not be a viable solution in his situation.
The antiviral agent, amantadine, was serendipitously found to improve PD symptoms
when a patient given the drug for influenza experienced a remission in her
90 Amantadine reduces all the symptoms of parkinsonian disability in
about 50% of patients, usually within days after starting therapy; however, early
trials indicated that amantadine efficacy might be limited by the development of
tachyphylaxis within 1 to 3 months.
91 Although the trials suggested reductions in
dyskinesias by up to 40%, previous evaluations of amantadine for the reduction of
dyskinesias have been limited by methodological concerns.
The pathophysiologic basis for the efficacy of amantadine in PD is not entirely
understood; it may augment dopamine release and possibly inhibit its reuptake.
Anticholinergic action has also been suggested. Excess glutamatergic activity has
been implicated in the pathophysiology of dopaminergic dyskinesias; amantadine has
been found to be an antagonist at N-methyl-D-aspartate (NMDA) receptors and to
93 Amantadine has consistently shown approximately
50% reductions in dyskinesia severity and duration, without adversely impacting
94–97 Two trials have evaluated long-term efficacy of amantadine
in patients with levodopa-induced dyskinesia after treatment for 6 months to 1 year.
These trials assessed for change in UPDRS motor examination and motor
complication subscores with amantadine washout over 3 weeks to 3 months. Those
discontinuing amantadine had deterioration in levodopa-induced dyskinesia
compared to the continuing group within a median time of 7 days suggesting the
possibility of continued benefit despite the tachyphylaxis suggested in earlier
99 Guidance suggests reserving consideration for amantadine use to those in
whom dyskinesia is not adequately managed on other therapies.
The decision to use amantadine in L.M. should be based on whether his
dyskinesias are deemed more problematic than his duration of off-time. If so,
amantadine should be started at 100 mg/day taken at breakfast; an additional 100-mg
dose can be taken with lunch 5 to 7 days after initiation. The dose can be increased to
a maximum of 300 mg/day; however, doses in excess of 200 mg/day are associated
with increased adverse effects and should be used cautiously. Amantadine is renally
excreted, and the dose should be reduced in patients with renal impairment.
dyskinesias that L.M. is experiencing are tolerable but the duration of off-time is
more problematic, then selection of another agent such as a COMT inhibitor or
MAO-B inhibitor may be more appropriate than the initiation of amantadine at this
Side effects of amantadine mainly involve the gastrointestinal (e.g., nausea,
vomiting) and CNS (e.g., dizziness, confusion, insomnia, nightmares, and
hallucinations). Patients receiving concomitant anticholinergic therapy may
experience more prominent CNS side effects.
100 Livedo reticularis, a rose-colored
mottling of the skin usually involving the lower extremities, can occur with
amantadine as early as 2 weeks after initiating therapy. The consequences of livedo
reticularis are entirely cosmetic, and discontinuation of therapy is unnecessary. Ankle
edema may be seen in association with livedo reticularis. Elevation of the legs,
diuretic therapy, and dosage reduction often alleviate the edema.
CATECHOL-O-METHYLTRANSFERASE INHIBITORS
COMT is an enzyme widely distributed throughout the body that is responsible for
the biotransformation of many catechols and hydroxylated metabolites, including
levodopa. When carbidopa, an inhibitor of aromatic AAD, is coadministered with
levodopa, the peripheral conversion of levodopa to dopamine via this pathway is
inhibited; as a consequence, the conversion of levodopa to 3-O-methyldopa (3-
OMD) by COMT is amplified and becomes the major metabolic pathway for
levodopa degradation. The metabolite 3-OMD lacks antiparkinsonian activity and
may compete with levodopa for transport into the circulation and brain. By
preventing its peripheral degradation, the therapeutic effect of levodopa can be
extended via inhibition of COMT.
Entacapone and tolcapone are selective, reversible, and potent COMT inhibitors
that increase the amount of levodopa available for transport across the blood–brain
barrier (Figure 59-4) to prolong its therapeutic effect. Use of these agents is
associated with increased on-time and a decrease in the daily levodopa dose.
The pharmacologic and pharmacokinetic effects of entacapone and tolcapone are
101–103 Two uncontrolled trials and one controlled evaluation
of patients with motor fluctuations newly placed on entacapone compared switching
patients to tolcapone versus continuing the newly started entacapone. These trials
alluded to the therapeutic benefits of tolcapone compared to entacapone; however,
tolcapone is associated with cases of fatal, acute fulminant liver failure. This has led
to stringent liver function monitoring requirements and limited clinical use. If
initiated, liver function monitoring should be performed at baseline and every 2 to 4
weeks for the first 6 months, followed periodically thereafter as clinically
101 Because of the risks for hepatotoxicity associated with tolcapone,
entacapone is the preferred COMT inhibitor and would be a good choice for L.M. if
he desires an increase in his on-time.
CASE 59-1, QUESTION 15: Six months after adjusting the frequency of his carbidopa/levodopa dose and
effective is entacapone for reducing the symptoms of PD?
Early initiation of a COMT inhibitor at the same time that levodopa is first
; theoretically, this strategy should provide more
stable plasma levels of levodopa and lessen pulsatile stimulation of striatal
dopamine receptors normally observed with intermittent levodopa dosing. This
strategy was tested in the Stalevo Reduction in Dyskinesia Evaluation in Parkinson
Disease (STRIDE-PD) study, a multicenter, double-blind study that randomly
assigned 747 patients to initiate either carbidopa/levodopa or
carbidopa/levodopa/entacapone 4 times daily.
104 Surprisingly, patients randomly
assigned to receive carbidopa/levodopa/entacapone actually had a shorter time to
onset of dyskinesia (hazard ratio: 1.29; P = 0.04) and increased dyskinesia frequency
at week 134 (42% vs. 32%; P = 0.02). These findings may have been confounded by
an increased use of dopaminergic therapy in the entacapone group. The findings of
the STRIDE-PD study do not support the early administration of entacapone in
combination with levodopa to reduce the occurrence of motor complications.
Pharmacologic and Pharmacokinetic Properties of Catechol-OMethyltransferase Inhibitors
Metabolism Glucuronidation; CYP3A4,
Isomerization, glucuronidation
Half-life (hours) 2–3 Biphasic; 0.4–0.7, 2.4
Time to reverse COMT inhibition
Maximal COMT inhibition at 200-mg
Increase in levodopa AUC 100% 35%
Increase in levodopa half-life 75% 85%
Dosing method TID, spaced 6 hours apart With every administration of
The efficacy and safety of entacapone as an adjunct to levodopa therapy in the
presence of motor complications was established in two pivotal multicenter,
randomized, double-blind, placebo-controlled trials.
had idiopathic PD with motor fluctuations, including wearing-off phenomena, despite
maximal tolerated doses of levodopa. In both trials, patients were randomly assigned
to receive either entacapone 200 mg or placebo (up to 10 doses/day) with each dose
In both trials, significant improvements in off-time
(approximately 1 hour), UPDRS scores (10% improvement), and levodopa doses
(reductions of approximately 80–100 mg/day) were consistent.
CASE 59-1, QUESTION 16: When should entacapone be initiated in L.M., and how should it be dosed?
Entacapone is approved for use as adjunctive therapy to levodopa for the treatment
of PD in patients experiencing wearing-off or end-of-dose deterioration. It is given
as one 200-mg tablet with each carbidopa/levodopa administration, up to eight
on individual formulations of carbidopa/levodopa and entacapone. If dyskinesias
occur, it may be necessary to lower the levodopa dose by approximately 10% to
25%, particularly if the patient is receiving more than 800 mg/day of levodopa.
Although pramipexole is being discontinued in L.M., he should still be monitored for
dyskinesias, especially during the first few weeks of therapy, as it may also be
necessary to lower his carbidopa/levodopa dose.
CASE 59-1, QUESTION 17: What are the adverse effects of entacapone, and how should they be
Most entacapone-induced adverse effects are consistent with increased levodopa
exposure. They include dyskinesias (50%–60%), dizziness (10%–25%), nausea
(15%–20%), and hallucinations (1%–14%).
106 Reducing the levodopa dosage by
entacapone include urine discoloration (11%–40%), diarrhea (10%), and abdominal
106 Urine discoloration (brownish orange) is attributed to entacapone
and its metabolites and is considered benign, but patients should be counseled
regarding this effect. The most common reason for withdrawal from clinical studies
and discontinuation of therapy was severe diarrhea (2.5%).
the STRIDE-PD study indicated that patients taking the combination of
carbidopa/levodopa/entacapone may be at an increased risk for cardiovascular
events (e.g., heart attack, stroke, and cardiovascular death) compared with those
taking carbidopa/levodopa, subsequent FDA analysis has found no increased risk.
MONOAMINE OXIDASE-B INHIBITORS
Selegiline may have a role as a symptomatic adjunct to levodopa in more advanced
disease. Studies have found improvement in the wearing-off effect in 50% to 70% of
patients and a reduction in as much as 30% in the total daily dose of levodopa
without improvements in on-time.
110 This improvement has also been shown to
arrive with an initial worsening of dyskinesis in 60% of treated patients which may
be counteracted with levodopa dose reductions. Selegiline has been shown to reduce
off-time by 32% (2.2 hours) compared with 9% (0.6 hours; P<0.001) for placebo in
a 12-week, randomized, multicenter, parallel-group, double-blind study, but was not
reproducible in an identical trial.
112 Authors hypothesize that this conflict may be
due in part to large and potentially variable placebo effects seen in PD trials. The
on–off effect is less responsive to the addition of selegiline.
Rasagiline has also been studied as an adjunct to levodopa in advanced disease.
When added to levodopa therapy, rasagiline can improve motor fluctuations,
reducing off-time by 1.4 hours and 1.8 hours (for the 0.5- and 1-mg/day groups,
respectively) compared with 0.9 hours for placebo.
mg/day and 1 mg/day of rasagiline had 0.49 hour (0.08–0.91; P = 0.02) and 0.94 hour
(1.36–0.51; P<0.001) less off-time compared with placebo. Significant
improvements were reported in the UPDRS subscores for ADLs in the off state and
motor performance in the on state, as well as clinician global assessments.
Dyskinesias were slightly worsened in the 1-mg/day group. As adjunctive therapy to
levodopa, rasagiline appears to provide similar benefit to entacapone.
Lasting effect in Adjunct therapy with Rasagiline Given Once daily (LARGO) study,
when compared with entacapone 200 mg administered with each levodopa dose,
rasagiline 1 mg/day reduced total daily off-time in a similar manner (decrease of
21% or 1.18 hours for rasagiline and 21% or 1.2 hours for entacapone).
of levodopa dose may be necessary if dyskinesias occur when rasagiline is added in
Safinamide (Xadago) was approved by the FDA in May 2017 as an adjunct to
carbidopa/levodopa for patients experiencing “off” episodes. It is not approved as
monotherapy and thus has not been previously discussed. The side effect profile is
similar to rasagiline (see Table 59-2). Patients should additionally be monitored for
visual changes as retinal detachment and loss of photoreceptor cells were noted in
animal studies. The list of contraindicated medications is extensive and should be
reviewed prior to starting therapy. Safinamide has a half–life of 20-26 hours, reaches
steady state in 5-6 days, and can be taken without regard to meals. It requires hepatic
dose adjustment but no renal dose adjustments. The extent of use in clinical practice
and eventual place in therapy are unknown at this time.
CASE 59-1, QUESTION 18: L.M. is now classified as Hoehn and Yahr
amantadine 100 mg twice daily, immediate-release carbidopa/levodopa 25 mg/250 mg 5 times daily, and
accompanied by troublesome dyskinesias. Most days he needs some assistance with ADLs. His cognitive
Two types of surgical therapies have been used in patients with advanced PD who
cannot be adequately controlled with medications. The first involves making an
irreversible surgical lesion in a specific location in the brain (e.g., posteroventral
pallidotomy or stereotaxic thalamotomy); the second involves surgical implantation
of a device that sends electrical impulses to specific parts of the brain (e.g., deep
brain stimulation [DBS]) (Figure 59-5). Posteroventral pallidotomy has been shown
to reduce dyskinesias on the contralateral side and may permit the use of higher
dosages of levodopa for managing rigidity and bradykinesia.
significant disadvantage is the need to make a lesion near the optic tract, which may
risk visual loss. Other possible risks of pallidotomy include weakness, paralysis, and
hemorrhage that can cause stroke and speech difficulty. Stereotaxic thalamotomy has
been shown to reduce symptoms of debilitating tremor and improve rigidity in
116 This intervention has eliminated contralateral tremor in 80% of
patients, and improvement has been sustained for up to 10 years. However, as with
pallidotomy, a disadvantage of thalamotomy is the need to make an irreversible
lesion in the basal ganglia that may limit the effectiveness of newer procedures
because they become available. Thus, DBS is now the preferred surgical method for
treating advanced PD that cannot be adequately controlled with medications. DBS
uses an implanted electrode in the brain, in either the subthalamic nucleus (STN) or
the globus pallidus interna (GPi), which is connected to a subcutaneously implanted
pacemaker. This permits delivery of high-frequency stimulation to the desired target.
Advantages of DBS include no need for an irreversible brain lesion, and it provides
flexibility for altering the target site and program stimulation parameters.
Philadelphia, PA: Lippincott Williams & Wilkins; 2000.)
The efficacy of DBS in advanced PD was shown in a two-part study of 255
patients with idiopathic PD responsive to levodopa but with persistent and disabling
117 Patients were randomly assigned to DBS or best medical therapy
and followed for 6 months. Patients receiving DBS gained a mean of 4.6 hours/day of
on-time without troubling dyskinesias compared with 0 hours/day for best medical
therapy (P<0.001). Additionally, 71% of patients receiving DBS experienced
clinically meaningful motor function improvements (≥5-point change in UPDRS
motor score) compared with only 32% of patients receiving best medical therapy
CASE 59-1, QUESTION 19: What surgical therapy would be most appropriate for L.M.?
L.M. appears to be an ideal candidate for DBS. Candidates for DBS should have
idiopathic PD and be levodopa-responsive, but continue to experience motor
complications or tremor despite optimal pharmacotherapeutic regimens. Ideally,
DBS should be avoided in patients with preexisting cognitive or psychiatric
problems owing to a slight risk of decline in cognition. No strict age limitation for
DBS exists, but patients younger than 70 years of age, such as L.M., appear to
recover from surgery more quickly and show greater motor improvements. Deep
brain stimulation of the STN consistently demonstrates marked reduction in the need
for escalating levodopa dosages compared with DBS of the GPi,
suggest other nonmotor symptoms such as visual processing speed and depression
may be affected more favorably when targeting the GPi.
Investigational Pharmacotherapy
QUESTION 1: K.B. is a 61-year-old woman who presents to the movement disorders clinic after referral
from her family doctor for a presumptive diagnosis of PD. She is Hoehn and Yahr
Antioxidants have been hypothesized to benefit patients with PD through their ability
to act as free radical scavengers. The most comprehensive evaluation of antioxidant
therapy for PD comes from the DATATOP study.
early PD were assigned to one of four treatment regimens: α-tocopherol (2,000
The primary endpoint was time to requirement of levodopa therapy. After
theoretic benefit, clinical data are lacking to support the routine use of α-tocopherol,
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