IntroductionParkinson disease (PD) is the

second most common neurodegenera-

tive disorder after Alzheimer disease.1

Approximately 1 million people in the

United States have PD, and 50,000 to

60,000 new cases are diagnosed annu-

ally.2 Although characterized by motor

symptoms, specifically tremor, rigidity,

bradykinesia, and postural instability,1

PD has an insidious onset. Nonmotor

symptoms may appear a decade or

more before the onset of motor symp-

toms and are often present long before

a definitive diagnosis of PD is made.3,4

Recognizing nonmotor symptoms and

early motor symptoms can enable phar-

macists to collaborate effectively with

physicians to intervene sooner and help

maintain patients’ quality of life.

PathophysiologyPD is caused by the deterioration

or loss of dopamine-producing neurons

in the brain.5 This damage and conse-

quent cell death occur in the substantia

nigra region for an estimated 6 years

before any motor symptoms develop.6

In other areas of the brain, such as the

medulla oblongata and pontine tegmen-

tum, this damage is believed to occur

even before the substantia nigra is

affected.7 By the time motor symptoms

appear, approximately 70% to 80% of

dopaminergic neurons have already

been lost.8

PD tends to be a disease of

older people (>65 years of age), and

rarely occurs before 40 years of age.9

Symptoms of early PD are often non-

specific and frequently attributed to

“aging.” Over time, people lose dopa-

minergic neurons in the substantia

nigra, but in individuals with PD, this

process is accelerated.10

Early Nonmotor Symptoms of PD

The most common early nonmotor

This issue of HIGHLIGHTS NEWSLETTER

is based on the educational session

Recognizing the Early Signs of

Parkinson Disease and Optimizing

Patient Outcomes presented by

Melody Ryan, PharmD, MPH, and

Stephen M. Setter, PharmD, DVM,

CDE, CGP, FASCP, at APhA2010, the

American Pharmacists Association

Annual Meeting & Exposition.

Dr. Ryan and Dr. Setter also served

as content reviewers for this publication.

Continuing

Pharmacy

Education

(CPE) Credit

Available!

September 2010

Volume 13

Number 2 HIGHLIGHTSN E W S L E T T E R

© 2010 by the American Pharmacists Association. All rights reserved. Printed in U.S.A.

symptoms of PD are constipation, rapid

eye movement sleep behavior disorder

(RBD), olfactory impairment, and car-

diac sympathetic denervation.11 RBD is

characterized by the unconscious acting

out of dreams. About half of patients

with RBD develop PD.12 Constipation

(<1 bowel movement daily) is associ-

ated with a nearly threefold increase

in risk of PD in men.13 Cardiac sym-

pathetic denervation probably occurs

in most if not all patients with PD.11

This condition is defined as a loss of

functional cardiac sympathetic nerve

terminals, represented by abnormal

blood pressure response to the Valsalva

maneuver. It also can be referred

to as long QT syndrome. Olfactory

impairment (altered sense of smell) is

a common early symptom that distin-

guishes PD from other parkinsonian

syndromes.14

Pharmacists may be able to rec-

ognize early PD by being aware of

the medications patients are using

or complaints they have related to

early nonmotor symptoms of PD. For

instance, a patient may purchase sever-

al over-the-counter (OTC) remedies for

constipation or have concerns about an

altered sense of smell. A patient with

cardiac sympathetic denervation may

Recognizing the Early Signs of Parkinson Disease and Optimizing Patient Outcomes

have episodic or persistent orthostatic

hypotension,15 which pharmacists can

recognize from complaints of fatigue,

lightheadedness, and dizziness, particu-

larly if these symptoms occur when the

patient arises from a seated or supine

position. These scenarios present phar-

macists with opportunities to question

patients about other nonmotor symp-

toms that may be early manifestations

of PD.

Cardinal Motor Signs and Other Symptoms of PD

Tremor, rigidity, bradykinesia,

and postural instability are the four

cardinal signs of PD16; however,

patients may have PD for years or

even decades before the signs develop.

These and other motor symptoms of

PD are typically unilateral at onset,

but usually become asymmetrically

bilateral with disease progression.

Tremor in PD commonly is more

prominent when a patient is still or

at rest. Rigidity is nearly universal in

people with PD. A patient with rigid-

ity may complain of muscle pain or

soreness. Bradykinesia is a slowness of

movement. Postural instability causes

Supplement to Pharmacy Today

10-181 Parkinsons's Disease.indd 1 8/20/10 1:19 PM

American Pharmacists Association

ACCREDITATION INFORMATION

The American Pharmacists Association is accredited by the

Accreditation Council for Pharmacy Education as a pro-

vider of continuing pharmacy education (CPE). The ACPE

Universal Activity Number assigned to this activity by the

accredited provider is 202-000-10-155-H01-P.

To obtain 1.5 hours of CPE credit (0.15 CEUs) for this activity, complete

the CPE exam and submit it online at www.pharmacist.com/education.

A Statement of Credit will be awarded for a passing grade of 70% or

better. You will have two opportunities to successfully complete the

CPE exam. Pharmacists who successfully complete this activity before

September 1, 2013, can receive credit.

Your Statement of Credit will be available online immediately upon

successful completion of the CPE exam.

DEVELOPMENT

This home-study CPE activity was developed by the American

Pharmacists Association.

SUPPORT

This activity is supported by an independent educational grant from Teva

Neuroscience.

DISCLOSURES

Melody Ryan, PharmD, MPH, declares no confl icts of interest or fi nancial

interests in any product or service mentioned in this activity, including

grants, employment, gifts, stock holdings, and honoraria.

Stephen M. Setter, PharmD, DVM, CDE, CGP, FASCP, has received

honoraria for serving on the speakers bureau for Teva and has received

research grant support from Teva.

APhA’s editorial staff declares no confl icts of interest or fi nancial interests

in any product or service mentioned in this activity, including grants,

employment, gifts, stock holdings, and honoraria.

This publication was prepared by Lauren Cerruto and Amanda Bach of

MedPen, Inc., on behalf of the American Pharmacists Association.

2

ACTIVITY PREVIEW

Parkinson disease (PD) activity is now known to start years before the

onset of characteristic motor symptoms. The availability of a neuroprotec-

tive or disease-modifying therapy would favor earlier initiation of treat-

ment, possibly before symptomatic treatment is needed. Pharmacists will

be better prepared to interact with physicians and patients by becoming

familiar with the latest data regarding the disease-modifying potential of

current therapies, as well as strategies for early diagnosis and manage-

ment of PD symptoms, adverse effects of PD medications, and drug

interactions.

LEARNING OBJECTIVES

At the completion of this activity, the pharmacist will be able to:

• Describe advances in the understanding of the pathophysiology

and pathology of PD.

• Analyze the importance of early diagnosis and management of

PD.

• Identify early nonmotor symptoms of PD.

• Differentiate the mechanisms of action for symptomatic therapies

available to treat early PD and describe potential neuroprotective

mechanisms of action for existing and emerging therapies.

• Evaluate current clinical trials of neuroprotective or disease-

modifying effects of PD therapies.

• Formulate options for helping patients maximize their quality

of life by managing PD symptoms and adverse effects of PD

medications.

ADVISORY BOARD

Melody Ryan, PharmD, MPH

Associate Professor

Department of Pharmacy Practice and Science

Department of Neurology

University of Kentucky College of Pharmacy

Lexington, Kentucky

Stephen M. Setter, PharmD, DVM, CDE, CGP, FASCP

Associate Professor

Department of Pharmacotherapy

Washington State University College of Pharmacy

Elder Services/Visiting Nurses Association

Spokane, Washington

Provider: American Pharmacists Association

Target Audience: Pharmacists

Release Date: September 1, 2010

Expiration Date: September 1, 2013

ACPE Number: 202-000-10-155-H01-P

CPE Credit Hours: 1.5 hours (0.15 CEUs)

ACPE Activity Type: Application-based

Learning Level: 2

Fee: There is no fee associated with this activity.

problems with balance and increases

the incidence of falls and therefore

fractures. Pharmacists should advise

such patients to have their bone health

evaluated and provide counseling about

calcium and vitamin D intake and other

strategies to improve bone health and

reduce fracture risk.

Other symptoms seen in the early

motor phases of PD include17:

• Diffi culty arising from a chair or turn-

ing in bed

• Masked facies (loss of facial expres-

sion due to muscle rigidity)

• Micrographia (small cramped hand-

writing)

• Hypophonia (low or muffl ed speech)

• Decreased arm swing on the affected

side when walking

• Stooped shuffl ing gait

• “Freezing” (inability to move when

attempting to walk)

• Painful foot cramps

Additional nonmotor symptoms that

are sometimes present both in early and

later stages of PD include cognitive

slowing, depression, anxiety, double

vision, and sialorrhea (drooling).

Differential DiagnosisIdiopathic PD must be differenti-

ated from drug-induced PD, because

the latter usually can be reversed by

discontinuing the offending medication.

A careful and complete medication his-

tory is necessary to determine whether

a particular drug is contributing to the

development of PD. TABLE 1 lists drugs

that commonly cause drug-induced

10-181 Parkinsons's Disease.indd 2 8/20/10 1:19 PM

3Highlights Newsletter: Recognizing the Early Signs of Parkinson Disease and Optimizing Patient Outcomes

PD,18-20 but note that most patients can

take these drugs without developing

PD-like symptoms.

may help reduce depression.22 On the

other hand, levodopa, dopamine

agonists, and anticholinergic agents

may exacerbate hallucinations/

dementia, and anticholinergic agents

may exacerbate constipation and

cognitive problems.22

Carbidopa/LevodopaMost PD therapies work by

countering the dopamine deficiency

associated with PD. Dopamine itself

does not cross the blood-brain barrier

and cannot be directly administered

as a PD therapy.23 Levodopa is an

inactive dopamine precursor that is

converted to dopamine.23 To prevent

peripheral metabolism of levodopa, it

is given with a decarboxylase inhibitor

(carbidopa, in the United States) that

does not cross the blood-brain bar-

rier.23 With the addition of carbidopa,

the levodopa dose can be decreased

by 75% and titrated more rapidly, and

there are fewer gastrointestinal adverse

effects.23

Available formulations of carbi-

dopa/levodopa in the United States

include oral tablets, sustained-release

tablets, and orally disintegrating tab-

lets (ODTs); a liquid formulation can

be compounded by adding water and

ascorbic acid to the drug.22 Standard

oral and ODT formulations are typi-

cally administered three to four times

daily, but are sometimes given more

frequently (up to every 2 hours).24 The

sustained-release formulation is admin-

istered two to four times per day.24

Carbidopa/levodopa remains the

most effective therapy for control of

nearly all classic PD motor symp-

toms.22 Carbidopa/levodopa is less

likely to alleviate freezing episodes,

postural instability, autonomic symp-

toms, mood disturbances, pain, sen-

sory symptoms, or dementia.22 Most

patients with PD use carbidopa/

levodopa at some point during the

course of their disease.22

With long-term use, carbidopa/

levodopa may cause adverse motor

effects in some patients, especially

those with young onset of PD and

those using higher levodopa doses.22

These adverse effects include dyski-

nesia (involuntary movements), early

wearing off at the end of the dosing

cycle, and “on-off” fluctuations in

which the patient shifts between good

mobility and motor dysfunction.22

Varying levels of levodopa in the

Think It Through: Case Vignette A 64-year-old woman comes to

the pharmacy accompanied by her hus-

band. She hands you a new prescription

for clonazepam and says her doctor

prescribed this medication to help her

sleep. Her husband explains that his

wife has vivid dreams and often acts

out her dreams, sometimes hitting out

with her arms and legs. He comments

on how tired they’ve both been. She

agrees, “I must be tired. I really seem

to be slowing down during the day.”

When asked whether she has any other

complaints or concerns, she reports

having muscle stiffness and back pain

during the last few months, which she

attributes to her restlessness during

the night. When the patient returns to

pick up her medication, she hands you

her shopping basket so you can also

ring up her other purchases, which

include tissues, acetaminophen, an

OTC laxative, a fiber supplement, and

toothpaste.

What signs and symptoms in this

case might make you conjecture

that the patient has early PD?

________________________________

________________________________

________________________________

See page 9 for answers.

It may be possible to differenti-

ate PD from both essential tremor and

drug-induced PD by noting the dif-

ferences among the three in symptom

presentation, symptom progression, and

response to drug therapy. Motor symp-

tom presentation is typically unilateral

in PD but is bilateral in drug-induced

PD and essential tremor.21 Essential

tremor tends to occur or worsen with

movement (action tremor) as opposed

to PD, which is a resting tremor

and often improves or subsides with

movement.21 Patients with PD experi-

ence progressive worsening, whereas

drug-induced PD is usually reversible.

Patients with essential tremor exhibit

no additional signs of PD.21 Response

to drug treatment with carbidopa/

levodopa is favorable in PD, but essen-

tial tremor does not respond to this

drug therapy.21

Current PD Therapies: Management of Early Motor Symptoms

Traditionally, both diagnosis and

treatment for PD were delayed until

the onset of bothersome motor symp-

toms. Clinicians’ increasing ability to

recognize PD at earlier stages raises

the question of whether PD therapy

should be started as early as possible or

delayed until needed for relief of motor

symptoms. Early initiation of therapy

as soon as symptoms begin to interfere

with daily activities has the advantage

of maximizing function, and theoreti-

cally may preserve basal ganglia com-

pensatory mechanisms.22 The decision

on when to initiate therapy should be

individualized based on the patient’s

need for symptomatic relief as well as

the therapy’s potential for disease mod-

ification (discussed in the next section),

short- and long-term tolerability, risk of

drug interactions, and cost. Early treat-

ment typically consists of carbidopa/

levodopa, a dopamine agonist, or a

monoamine oxidase type B (MAO-B)

inhibitor; other available options for

initial monotherapy include amantadine

or an anticholinergic agent.

There are few studies on the effect

of PD therapies on specific nonmotor

symptoms, although behavior, mood,

activities of daily living, and symp-

toms such as salivation and speech are

assessed in the PD rating scales used to

study many of these medications. There

is some evidence that PD therapies

Table 1. Common Offenders in Drug-Induced Parkinson Disease

Antipsychotics

• Haloperidol

• Chlorpromazine

• Thioridazine

• Risperidone

• Olanzapine

Gastrointestinal Agents

• Metoclopramide

• Prochlorperazine

Dopamine Depletors

• Alpha-methyldopa

• Reserpine

• Tetrabenazine

Drug Combinations

• Amitriptyline/perphenazine

Source: References 18–20.

10-181 Parkinsons's Disease.indd 3 8/20/10 1:20 PM

American Pharmacists Association4

bloodstream and the brain, attribut-

able to levodopa’s short half-life, may

account for these motor fluctuations.24

Fluctuations can be diminished by

using sustained-release carbidopa/

levodopa or adding a catechol-O-meth-

yltransferase (COMT) inhibitor (e.g.,

entacapone) or an MAO-B inhibitor.

Dyskinesias can be reduced by slightly

decreasing the levodopa dose.22 To

obtain the right balance, patients can

make small temporary adjustments in

their carbidopa/levodopa dose depend-

ing on the activities they have planned

for the day. For example, they may

need a little more medication for a day

full of activities or a little less for a day

spent sitting in a car for a long ride.

Because of the risk of motor com-

plications, many clinicians prefer to

reserve carbidopa/levodopa for patients

who have moderate to severe symp-

toms, and to use alternate therapies for

early management of PD, while it is

still mild. The decision to use carbi-

dopa/levodopa should be individualized

because some patients with bothersome

motor symptoms would rather tolerate

the dyskinesias in order to have better

mobility than to have less control of

PD motor symptoms.

Dopamine AgonistsDopamine agonists directly stimu-

late dopamine receptors.24 The older

ergot-derived dopamine agonists bro-

mocriptine and pergolide were associ-

ated with significant adverse effects

including heart-valve abnormalities.

Pergolide has been removed from

the market; bromocriptine remains

available but is rarely used. Newer

nonergot-derived oral dopamine ago-

nists (i.e., pramipexole and ropinirole)

have not been associated with these

adverse effects and are used as initial

monotherapy or adjuncts to levodopa24

or (off-label) as adjuncts to MAO-B

inhibitors. Pramipexole and ropinirole

are each available in standard oral

formulations, for administration three

times daily,25,26 and in extended-release

formulations, for once daily admin-

istration.27,28 In more advanced PD,

apomorphine, an injectable dopamine

agonist, is used as a “rescue” therapy

for treating severe “off” episodes, and

must be taken with antiemetic medica-

tions to reduce significant nausea.24 A

transdermal dopamine agonist, rotigo-

tine, was approved by the U.S. Food

and Drug Administration (FDA); how-

ever, it has been temporarily withdrawn

from the market because of crystal

formation in the patches. A new formu-

lation is now being developed.29

Dopamine agonists provide good

control of motor symptoms, may delay

motor complications and the need to

initiate carbidopa/levodopa, and allow a

lower dose of carbidopa/levodopa to be

used.22,30 A meta-analysis of 29 clini-

cal trials found that PD symptom con-

trol (based on clinician-rated disability

scales) was not as good with dopamine

agonists as with carbidopa/levodopa.31

Dopamine agonists were less likely to

cause dyskinesias, dystonias, or motor

fluctuations but more likely to cause

nonmotor adverse effects (e.g., edema,

somnolence, constipation, dizziness,

psychosis, nausea) compared with

carbidopa/levodopa.31

MAO-B InhibitorsAnother strategy to address

dopamine depletion in PD is to keep

available dopamine around longer.

Monoamine oxidase (MAO) is one of

the enzymes responsible for breaking

down dopamine. Therapies that block

MAO slow dopamine’s metabolism,

leaving more dopamine available in the

brain.24 Selective MAO-B inhibitors

provide another therapeutic option for

patients with mild motor disability and

early PD.22,30 Rasagiline is an FDA-

approved MAO-B inhibitor for use as

initial monotherapy,32 and selegiline

is commonly used off-label for this

indication.22 Both are also approved

as adjuncts to levodopa. Rasagiline

standard oral tablets are administered

once daily.32 Selegiline is available in

a standard oral formulation with once-

or twice-daily administration33 and an

ODT formulation given once daily.34

A transdermal selegiline formulation is

available for treatment of depression35;

however, it is not approved for treat-

ment of PD.

Selegiline proved superior to

placebo in a randomized trial,36 but

it is largely perceived to offer weaker

symptomatic benefits compared with

levodopa or dopamine agonists—a

perception supported by a meta-

analysis of two studies comparing

selegiline with dopamine agonists

and levodopa.37 Rasagiline’s use as

initial monotherapy is supported by

results from the Rasagiline Mesylate

in Early Monotherapy for Parkinson’s

Disease Outpatients (TEMPO)38 and

Attenuation of Disease Progression

With Azilect [Rasagiline] Given Once-

Daily (ADAGIO)39 studies, both of

which showed significant benefit

versus placebo in terms of effect on

Unified Parkinson’s Disease Rating

Scale (UPDRS) scores over time. (The

UPDRS is a standardized clinician rat-

ing scale for disability associated with

PD.40) Additional data from these trials

suggesting disease-modifying activity

are discussed in the next section. A

recent publication reported on long-

term data from the TEMPO study.41

Of patients in the trial at 2 years, 46%

were maintained on rasagiline mono-

therapy and the remainder received

additional therapies. By 5.4 years,

only 25% of patients progressed to

Hoehn and Yahr stage 3.41 (The Hoehn

and Yahr scale uses a 5-point system

for staging PD.42) There are no data

comparing rasagiline with carbidopa/

levodopa or dopamine agonists, but

clinically, the MAO-B inhibitors as a

class tend to have modest effects on PD

motor symptoms.43

Anticholinergic AgentsDopamine deficiency in PD

appears to disturb the balance between

acetylcholine and dopamine neuro-

transmissions in the basal ganglia.22

Although acetylcholine levels are not

technically elevated in PD, reducing

these levels restores the dopamine-

acetylcholine balance. Anticholinergic

agents (e.g., trihexyphenidyl, benztro-

pine) are therefore sometimes used,

particularly in younger patients

(<60 years of age) whose predominant

PD symptom is resting tremor. They

are less effective for controlling other

PD symptoms.22 Anticholinergic

agents are administered two to three

times daily.24 Anecdotally, some pa-

tients take them only as needed, such

as in social situations during which

tremor is particularly bothersome.

AmantadineAmantadine was first developed as

a treatment for influenza but was ser-

endipitously discovered to have activ-

ity in PD.24 Its mechanism of action

may include stimulation of dopamine

release or dopamine receptors, block-

ade of dopamine reuptake, and possibly

anticholinergic activity.22 Amantadine

is used as initial monotherapy for

newly diagnosed patients with mild

PD symptoms. Its beneficial effect

10-181 Parkinsons's Disease.indd 4 8/20/10 1:20 PM

5Highlights Newsletter: Recognizing the Early Signs of Parkinson Disease and Optimizing Patient Outcomes

5

tends to diminish after a few weeks to

months.24 Amantadine is available in

capsules and oral suspension, adminis-

tered two to three times daily.24

Treatment of Early PD: Potential for Neuroprotection?

In the earliest stages of PD, treat-

ment is sometimes considered for the

purpose of disease modification—that

is, to slow the progression of PD. No

therapy has been unequivocally shown

to prevent loss of dopaminergic neu-

rons, and even clinical disease modifi-

cation continues to be debated. Studies

of neuroprotection have relied on sur-

rogate biomarkers, including neuro-

imaging of the nigrostriatal system,

and on modified clinical trial designs

such as posttreatment washout periods

or delayed-start designs (FIGURE 1).

In a posttreatment washout study, it is

assumed that any residual benefit seen

during the washout period would be

attributable to neuroprotection; howev-

er, there is much debate regarding the

duration of the washout period required

to assess such effects. Delayed-start

designs compare early versus later

initiation of treatment. A disease-

modifying therapy would be expected

to show a sustained advantage with

early treatment initiation even after all

participants were receiving therapy in

the later phase.

Clinical trials to assess neuropro-

tection of ropinirole and pramipexole

have used neuroimaging—such as 18F-dopa positron emission tomogra-

phy (FD-PET) or 2β-carboxymethoxy-

3β(4-iodophenyl)tropane (β-CIT)

uptake on single-photon emission com-

puted tomography (SPECT)—as a bio-

marker of dopaminergic activity in the

nigrostriatum.44,45 These neuroimaging

trials suggest that loss of function (and

presumably loss of dopaminergic neu-

rons) in this area of the brain is slower

in patients taking dopamine agonists

compared with levodopa, despite the

ability of levodopa to provide greater

symptomatic relief.44,45 In contrast to

the neuroimaging data, however, results

of a delayed-start trial of pramipexole

did not show a disease-modifying

effect.46

MAO-B inhibitors, particularly

rasagiline, hold promise as potential

disease-modifying agents. Two

delayed-start trials (TEMPO and

ADAGIO) evaluated the disease-

modifying potential of rasagiline.38,39

In both studies, rasagiline, at its

approved dose of 1 mg/d, had a greater

impact on disability when started ear-

lier than it did after a 6- to 9-month

delay.38,39 (Disability was measured

with the UPDRS.) This finding sug-

gests that rasagiline may have more

than symptomatic benefit: it also may

modify the course of the disease.

However, only the TEMPO trial con-

firmed similar benefit with a higher

off-label dose of rasagiline 2 mg/d.38

The ADAGIO study required that three

end points all be met to satisfy a posi-

tive result: (1) superiority to placebo

in the rate of change of UPDRS scores

between weeks 12 and 36, (2) superi-

ority to delayed-start treatment in the

change in UPDRS score between base-

line and week 72, and (3) noninferior-

ity to delayed-start treatment in the rate

of change in UPDRS score between

weeks 48 and 72.39 Rasagiline 1 mg/d

met all three end points, demonstrating

that patients who start treatment later

do not “catch up” to those who start

earlier. Rasagiline 2 mg/d met only the

first and third end points,39 and thus

did not meet the full criteria for disease

modification. The investigators specu-

lated that a greater symptomatic benefit

with the higher dose may have masked

its disease-modifying activity.39

The Deprenyl [Selegiline] and

Tocopherol Antioxidative Therapy

of Parkinsonism (DATATOP) trial

compared selegiline (10 mg/d) plus

placebo, vitamin E (2000 IU/d) plus

placebo, selegiline plus vitamin E at

these same doses, and double placebo

in 800 patients with early PD.36,47

There was no benefit to vitamin E, but

use of selegiline slowed progression

of disability, significantly delaying the

time until levodopa was needed by an

average of almost 9 months.36 Initially,

this result was attributed at least in part

to a neuroprotective effect, because

symptomatic benefits of selegiline

were thought to be modest,47 and even

patients who initially had no improve-

ment in total UPDRS scores on treat-

ment still showed a delay in time until

need for levodopa.36

After the benefit of selegiline was

established, the DATATOP protocol Graphics courtesy of Melody Ryan, PharmD, MPH.

Figure 1. Drug Trial Designs to Evaluate Neuroprotection

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10-181 Parkinsons's Disease.indd 5 8/20/10 1:20 PM

American Pharmacists Association6

E, coenzyme Q10, or creatine because

they have heard that these therapies

can be beneficial in PD. As shown in

the DATATOP trial, vitamin E does

not alter the course of PD.36 Similarly,

a randomized, prospective, phase II

trial of coenzyme Q10 found it safe

and well tolerated, but did not find sig-

nificant effects on disability compared

with placebo in patients with midstage

PD.52 Coenzyme Q10 is currently being

assessed in a placebo-controlled phase

III trial.53 Vitamin C is a weak COMT

inhibitor, and in a six-patient study

produced modest functional improve-

ments54; however, large-scale con-

trolled trials have not been performed.

Small studies suggest that vitamin C

also may alter levodopa pharmacoki-

netics, increasing the area under the

curve and peak drug concentration,

while reducing the time to peak drug

concentration.55 In an 18-month phase

II pilot trial, neither creatine nor mino-

cycline met the threshold for futility

with regard to slowing progression of

PD-related disability.56 Creatine is cur-

rently being assessed in a large-scale,

placebo-controlled, phase III clinical

trial.57

Additional Adverse Effects of PD Therapies

In addition to the risk of motor

complications, PD therapies have a

number of other adverse effects that

require careful monitoring and man-

agement. Carbidopa/levodopa and

dopamine agonists share dopaminergic

adverse effects such as nausea, light-

headedness/dizziness, somnolence,

fatigue, constipation, sleep disturbanc-

es, confusion, and hallucinations. It is

often difficult to determine whether

some of these symptoms are PD related

or drug induced. Orthostatic hypoten-

sion is a common adverse effect of

many PD medications, even in patients

who were previously hypertensive.

Dopamine agonists are more

likely than carbidopa/levodopa to cause

excessive daytime sleepiness, visual

hallucinations, confusion, leg edema,

and compulsive behaviors (e.g., exces-

sive eating, shopping, gambling, or

sexual urges).24 Leg edema is often

mistaken for a sign of cardiac dys-

function. Dyskinesias may occur in

patients taking dopamine agonists but

are less common than with carbidopa/

levodopa.24

was modified to withdraw treatment,

and patients were reassessed after a

2-month washout. Patients treated

with selegiline experienced mild but

significant worsening in the motor

score of the UPDRS at 1 and 2 months

compared with patients who had not

received selegiline.36 After that phase

of the trial, all DATATOP participants

were offered open-label selegiline

therapy, tantamount to a delayed-start

design. Among the subgroup of patients

not yet taking levodopa, those who

had received selegiline since the start

of the trial (the “early-start group”)

had no sustained advantage over those

who started selegiline during the later

open-label phase (the “delayed-start

group”).48 Among the subgroup of

patients who were taking levodopa

during the open-label phase, earlier

initiation of selegiline did not reduce

motor complications (wearing off,

dyskinesias, on-off episodes, freezing)

compared with later initiation of selegi-

line.49 Thus, later data from DATATOP

do not show evidence of disease

modification; however, continued use

of selegiline may nonetheless provide

clinical benefit. Some of the patients

taking levodopa and selegiline were

rerandomized to either continue sele-

giline or switch to placebo. Continued

selegiline for up to 7 years slowed the

rate of motor decline and reduced the

risk of freezing, but increased the risk

of dyskinesias compared with discon-

tinuation of selegiline.50

Questions have been raised regard-

ing whether levodopa damages rather

than preserves dopaminergic neu-

rons.22 This question was considered

in the Earlier Versus Later Levodopa

(ELLDOPA) study, which compared

carbidopa/levodopa (12.5/50 mg,

25/100 mg, or 50/200 mg administered

three times daily) with placebo and

concluded with a 2-week washout

period.51 During treatment, levodopa

provided a clear symptomatic effect

(FIGURE 2). During the washout,

UPDRS scores worsened in the levodo-

pa group, but did not reach the placebo

group’s level. These clinical findings

contradict the hypothesis of levodopa

being neurotoxic; however, neuroim-

aging data showed that the levodopa

groups had a faster rate of decline in

β-CIT uptake on SPECT. The imaging

data may signify greater degenera-

tion of dopaminergic neurons in the

levodopa group. It is not clear how to

reconcile the discrepancy between the

clinical findings and imaging data.51

Patients with PD often take alter-

native therapies such as vitamins C and

Figure 2. ELLDOPA Trial: Changes in Total Scores on the UPDRS From

Baseline Through Evaluation at Week 42

Daily dosages of levodopa shown were administered in three divided doses.

ELLDOPA = Earlier Versus Later Levodopa; UPDRS = Unified Parkinson’s Disease Rating Scale.

Source: Reference 51. Parkinson Study Group. Levodopa and the progression of Parkinson’s disease. N Engl J Med. 2004;351:2498–508. Copyright © 2004 Massachusetts Medical Society. All rights reserved. Reprinted with permission.

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7Highlights Newsletter: Recognizing the Early Signs of Parkinson Disease and Optimizing Patient Outcomes

crisis occurs when vasoactive dietary

tyramine is allowed to reach the

bloodstream.60 It has been dubbed

the “cheese reaction” because aged

cheese has among the highest tyra-

mine levels of all foods. Tyramine is

normally metabolized by MAO type

A (MAO-A) before it reaches the

circulation,60 so inhibition of MAO-A

increases the risk of this adverse

event. At recommended doses, both

rasagiline and selegiline are selective

for MAO-B and unlikely to cause

the cheese reaction, therefore dietary

restriction of tyramine is largely

not required with these agents.32,33

Nonetheless, patients taking MAO-B

inhibitors may want to avoid foods

that have a very high tyramine con-

tent.32,33

MAO-B Inhibitors and Antidepressants

Concurrent use of an MAO

inhibitor with antidepressants or

medications that affect serotonin lev-

els can increase the risk of serotonin

syndrome. The most serious reactions

have occurred with therapies that

inhibit MAO-A, including nonselec-

tive MAO inhibitors.61 Serotonin

syndrome is very rare with selective

MAO-B inhibitors and is listed as a

warning or precaution in the product

labeling but not as a contraindica-

tion.24 In clinical practice, MAO-B

inhibitors and antidepressants are

commonly used together. Pharmacists

should discuss with the prescriber

the risks and benefits of concomitant

administration of MAO-B inhibi-

tors and antidepressants for a spe-

cific patient. Use of meperidine,

tramadol, methadone, propoxyphene,

dextromethorphan, St. John’s wort,

and other MAO inhibitors (selec-

tive or nonselective) concurrent with

MAO-B inhibitors is contraindicated,

however.32-34 See www.pharmacyto

day.org/pdf/2010/CE/CE_Jul2010.pdf

for more information on serotonin

syndrome in patients taking MAO-B

inhibitors and antidepressants.

PD Therapies and Cytochrome P450 Enzymes

The hepatic enzyme cytochrome

P450 (CYP) 1A2 metabolizes ropin-

irole and rasagiline. As a result,

CYP1A2 inhibitors such as cipro-

floxacin, fluvoxamine, and cimetidine

may increase their plasma concentra-

tions. Conversely, CYP1A2 inducers

such as omeprazole or cigarette smok-

ing may increase their clearance.26,32

When used with a CYP1A2 inhibitor,

the rasagiline dose should not exceed

0.5 mg/d.32

Pramipexole and Renally Secreted Drugs

Because pramipexole is excreted

renally by cationic tubular secretion,

its elimination is reduced by other

drugs that either inhibit or compete for

cationic tubular secretion; such drugs

include cimetidine, verapamil, proben-

ecid, ranitidine, diltiazem, quinine, and

triamterene.27

Investigational Therapies for PD

As shown in TABLE 2,62-75 a num-

ber of new therapies for PD are now in

phase III clinical trials, although most

of them are being developed as adjunc-

tive treatments for later-stage PD. In

addition, a phase III placebo-controlled

trial of embryonic dopamine cell

implant surgery is ongoing.76

Maximizing Quality of Life by Managing Non-motor Symptoms and Adverse Drug Effects

Nonmotor symptoms and adverse

effects of PD medications can have a

tremendous impact on patients’ qual-

ity of life and should be addressed in

encounters between pharmacists and

patients.

Orthostatic Hypotension Orthostatic hypotension is a

common symptom of PD that can be

exacerbated by dopaminergic medica-

tions.22 Signs of orthostatic hypoten-

sion include lightheadedness, fatigue,

unsteadiness, headache, neck tightness,

and cognitive slowing.77 The first step

in managing orthostatic hypotension

is to taper off antihypertensive drugs

and other non-PD drugs if necessary.

Treatment with fludrocortisone (0.1–

0.4 mg/d) or midodrine (2.5–30 mg/d)

may raise blood pressure, and intrana-

sal desmopressin (5–40 µg at bedtime)

may be used as an adjuvant to fludro-

cortisone as needed.22 Patients should

be advised to increase salt intake (with

their physician’s approval), avoid lying

prone, wear waist-high stockings,

increase fluid intake, move slowly

What Do You Think?

Is it best to wait until a patient has

particularly bothersome motor symptoms

before initiating treatment for PD, or

should therapy be initiated as early as

possible? Take a moment to list possible

pros and cons of early PD treatment:

Pros Cons

________________ ________________

________________ ________________

See page 9 for answers.

Adverse effects of rasagiline

include flu-like symptoms, arthralgia,

depression, dyspepsia, infection, and

headache.32,58 Selegiline’s adverse

effects include nausea, musculoskeletal

injuries, non–life-threatening cardiac

arrhythmias, and elevated serum ami-

notransferase levels.36 Unlike selegiline

ODT and rasagiline, the standard oral

formulation of selegiline is metabolized

to amphetamine and methamphet-

amine.24 These amphetamine metabo-

lites may give some patients the feeling

of having an “energy” boost, which

can be an advantage, but can also con-

tribute to sleep abnormalities such as

insomnia,22 jitteriness, and confusion.24

Many clinicians advocate dosing sele-

giline in the morning and early evening

to avoid interference with sleep.

Amantadine can cause nausea,

lightheadedness, insomnia, confusion,

and hallucinations.24 Its neuropsychiat-

ric adverse effects tend to limit its use

in older patients and those with demen-

tia. Rarely, amantadine causes livedo

reticularis, a reversible mottling of the

skin, usually on the legs, which does

not necessarily require treatment dis-

continuation.24 Amantadine is cleared

renally and the dose must be adjusted

according to creatinine clearance if the

patient has renal impairment.59

Anticholinergic agents can cause

memory impairment, confusion, hal-

lucinations, sedation, dysphoria, dry

mouth, blurred vision, and urinary

retention.22,24 These agents are typi-

cally used in younger patients with PD,

because older patients tend to tolerate

the adverse effects poorly.24

Understanding Potential Food and Drug InteractionsMAO-B Inhibitors and “Cheese Reaction”

A potentially fatal hypertensive

10-181 Parkinsons's Disease.indd 7 8/20/10 1:21 PM

American Pharmacists Association8

when rising or lifting the head, and

monitor blood pressure at home.22,78

ConstipationConstipation, a common and often

early symptom of PD, can be particu-

larly bothersome to patients. Patients

should be advised to increase fluid

intake, dietary fiber, and exercise.22 If

these measures are insufficient, patients

can try OTC stool softeners22 or isos-

motic macrogol (polyethylene glycol)77

under physician guidance. There are

anecdotal reports of some patients

benefitting from homemade natural

laxatives that include blended prunes,

raisins, figs, senna tea, sugar, and juice.

Bladder DysfunctionPatients who frequently awaken

to urinate may have to curtail fluid

intake after the evening meal.22

Pharmacologic therapies used in the

management of bladder dysfunction

include peripherally acting anticholin-

ergics such as oxybutynin (5–10 mg

at bedtime or three times daily), pro-

pantheline (7.5–15 mg at bedtime

or three times daily), or tolterodine

tartrate (1–2 mg twice daily based on

individual response and tolerability or

long-acting formulation at 4 mg/d).22

If those therapies are ineffective, hyo-

scyamine (0.15–0.30 mg at bedtime or

on a four times daily schedule) may be

considered.22 Patients with persistent

bladder problems should be referred to

a urologist.

DysphagiaPatients with PD frequently have

difficulty swallowing. Pharmacists can

educate such patients to “lube the tube”

by drinking to lubricate the esophagus

before swallowing pills, or switch

to ODT formulations if available.24

Drinking and eating may be facilitated

by using a food-thickening prod-

uct in liquids and pureeing foods.79

Scheduling meals during “on” times

also can be helpful.22

Sialorrhea Sialorrhea (drooling) can be

socially embarrassing and can increase

the risk of aspiration pneumonia or

skin erosions.22 Strategies that may

help prevent drooling include gum

chewing, use of 1 to 2 drops of atro-

pine ophthalmic solution placed under

the tongue to dry out the mouth, oral

anticholinergic agents, and botulinum

toxin injections into the salivary

gland.22,24

NauseaNausea is a potential adverse

effect of most PD therapies. Nausea

associated with carbidopa/levodopa

may be alleviated by adding single-

agent carbidopa23 or taking the dose

with food.22,79 Other strategies for

managing nausea include adding tri-

methobenzamide to the drug regimen24

and advising patients to ingest ginger

products (e.g., ginger ale, ginger tea,

gingersnaps).79 The following medica-

tions should be avoided because they

may cause PD-like symptoms: meto-

clopramide, phenothiazine, prometha-

zine, perphenazine.18,24

Sleep Abnormalities and Excessive Daytime Sleepiness

Sleep abnormalities associated

with PD include fragmented sleep (due

to PD symptoms), RBD, periodic limb

movements, restless legs syndrome,

and sleep apnea.80 The complexities

of sleep abnormalities require man-

agement by a neurologist or a sleep

specialist to determine the best course

of action for the individual patient.

Anticholinergics such as diphenhy-

dramine may facilitate sleep but can

cause constipation or cognitive impair-

ment.81 Clonazepam or melatonin is

often used for RBD; however, data in

patients with PD are lacking.77

Excessive daytime sleepiness

may be a result of interrupted sleep

due to sleep abnormalities but also

may be associated with advanced age,

advanced PD, or use of dopaminer-

gic medication. This symptom may

be transient or chronic. Patients who

are excessively sleepy during the day

should be advised to take short naps,

consider increasing caffeine intake (if

not contraindicated), and increase day-

time stimulation. In addition, if sudden

sleep episodes occur without warning,

patients should stop driving79 and tell

their physician. Sedating medications

and the dose of dopamine agonists

should be reduced.22 Modafinil offers

modest benefits in promoting wakeful-

ness.22

Psychosis and DementiaPsychosis in patients with PD

may include disorientation, hallucina-

tions, and delusions. The first step is

to simplify the patient’s medication

regimen.22 Discontinue unnecessary

non-PD medications.22 Gradually

reduce the dose or discontinue PD

medications—stopping levodopa

last.24,79 If these steps are insufficient

to reverse the psychosis, consider treat-

ment with quetiapine or clozapine.79,82

Clozapine is preferred for treatment

of hallucinations, but is associated

with agranulocytosis, necessitating

regular white blood cell count monitor-

ing.83 Chlorpromazine, haloperidol,

olanzapine, perphenazine, risperidone

and aripiprazole may worsen PD.22

Table 2. Investigational Therapies in Phase III Trials for PD

Therapy Description

Developed for initial treatment of early PD

IPX066a Extended-release carbidopa/levodopa that produces more rapid and more sustained concentrations with reduced dosing frequency

Pardoprunoxb Partial dopamine D2/3 receptor agonist and serotonin 5-HT1A agonist

Developed for use in advanced PD

Lisuride Ergotamine dopamine D2 receptor agonist and serotonin 5-HT2B antagonist, given continuously via subcutaneous pump

Sumanirolec Highly selective dopamine D2 receptor agonist

Carbidopa/levo- dopa intestinal gel

Carbidopa/levodopa administered continuously via pump to the duodenum

Istradefylline Selective adenosine A2A receptor antagonist

Safinamide Selective MAO-B inhibitor

a IPX066 is also being investigated for conversion from regular carbidopa/levodopa or carbidopa/levodopa/entacapone in advanced PD.

b Pardoprunox is also being investigated as an adjunct to levodopa. c Sumanirole did not meet criteria for noninferiority to ropinirole as monotherapy in early PD.

MAO-B = monoamine oxidase type B; PD = Parkinson disease.

Source: References 62–75.

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9Highlights Newsletter: Recognizing the Early Signs of Parkinson Disease and Optimizing Patient Outcomes

PD patients with dementia may ben-

efit from rivastigmine, donepezil, or

memantine.22

DepressionNo antidepressant has been

proven more effective than any other

in patients with PD, so the decision

of which drug to prescribe should be

based on the preferences and response

of the individual patient. Selective

serotonin reuptake inhibitors are com-

monly used,22 but rasagiline clinical

trials did not allow concomitant use of

fluoxetine and fluvoxamine with rasa-

giline. 32 Tricyclic antidepressants can

be effective but may have anticholiner-

gic adverse effects.22 If antidepressants

are used concurrently with an MAO-B

inhibitor, the patient should be moni-

tored carefully for serotonin syndrome.

Ask patients what they know about

their depression and advise them to

undergo counseling or join a support

group, discuss their symptoms with

their family and others they trust for

support, and exercise regularly.

PainPain in PD may result from limb

rigidity, dystonia, or primary central

pain. Treatment is dependent on the

source of pain, which must first be

identified. Medications that may be

used include OTC analgesics, muscle

relaxants, dopaminergic medications,

and benzodiazepines.24

ConclusionNonmotor symptoms such as

olfactory dysfunction, RBD, constipa-

tion, and cardiac sympathetic denerva-

tion are often the first manifestations

of PD. Unfortunately, these symptoms

are nonspecific, which complicates

early diagnosis. There is ongoing con-

troversy regarding whether treatment

should be initiated for early PD—that

is, PD diagnosed either before the

onset of motor symptoms or at a stage

when motor symptoms are mild and

not particularly bothersome to the

patient. Data on rasagiline is suggestive

of a disease-modifying effect, lead-

ing some clinicians to initiate therapy

as early as possible. When symptoms

begin to interfere with daily living and

become bothersome, many clinicians

prefer to start with an MAO-B inhibitor

or dopamine agonist, reserving carbi-

dopa/levodopa for patients with moder-

ate to severe symptoms. The decision

on when to start treatment and which

treatment to use is best individualized,

taking into account the patient’s symp-

toms and concomitant medications,

as well as drug efficacy, potential for

disease modification, and tolerability.

Comprehensive management of PD

also includes management of nonmotor

symptoms and adverse effects of PD

medications. Pharmacists can play an

important role in ensuring that symp-

toms are optimally controlled while

preventing, recognizing, and managing

adverse effects and drug interactions.

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Answers to “Think It Through”The following are suggestive of early

PD in this case:

Age, RBD, the OTC laxative and fiber

supplement (suggesting that the patient

is constipated), her reported feeling of

“slowing down” (which could be brady-

kinesia), and muscle stiffness and back

pain (which could be effects of rigidity).

Answers to “What Do You Think?” No treatment has definitively been

proven to be neuroprotective, there-

fore clinicians must form their own

opinions about the risk:benefit ratio

of early therapy. Advantages of

early therapy might include delay in

progression of disability, reduction

in PD symptoms, and maximized

function. The disadvantages include

possible adverse effects for specific

medications, the cost of the medica-

tion, and the challenges of adher-

ence to the medication. Pharmacists

can work with patients and phy-

sicians to help identify the best

therapy for specific patients and

manage these issues. Treatment of

mild to moderate symptoms is often

prudent when symptoms begin to

interfere with daily activity.

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American Pharmacists Association10

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55. NagayamaH,HamamotoM,UedaM,etal.TheeffectofascorbicacidonthepharmacokineticsoflevodopainelderlypatientswithParkinsondis-ease.Clin Neuropharmacol.2004;27:270–3.

56. NINDSNET-PDinvestigators.ApilotclinicaltrialofcreatineandminocyclineinearlyParkinsondisease:18-monthresults.Clin Neuropharmacol.2008;31:141–50.

57. NET-PDLS-1creatineinParkinson’sdisease.ClinicalTrials.govWebsite.Availableat:http://www.clinicaltrial.gov/ct2/show/NCT00449865?term=creatin.AccessedJune7,2010.

58. ParkinsonStudyGroup.AcontrolledtrialofrasagilineinearlyParkinsondisease.TheTEMPOStudy.Arch Neurol.2002;59:1937–43.

59. Symmetrel[packageinsert].ChaddsFord,PA:EndoPharmaceuticals;May2007.

60. McCabe-SellersB,StaggsCG,BogleML.Tyramineinfoodsandmonoamineoxidaseinhibi-tordrugs:acrossroadwheremedicine,nutrition,pharmacy,andfoodconverge.J Food Composition Analysis. 2006;19:S58–65.

61. BoyerEW,ShannonM.Theserotoninsyndrome.N Engl J Med.2005;352:1112–20.

62. ImpaxPharmaceuticalscompletesenrollmentinAPEX-PDphaseIIItrialofIPX066inParkinson’sdisease[pressrelease].ImpaxLaboratories;April15,2010.Availableat:http://phx.corporate-ir.net/phoenix.zhtml?c=67240&p=irol-newsArticle&ID=1413444&highlight=.AccessedJune7,2010.

63. BronzovaJ,SampaioC,HauserRA,etal.Double-blindstudyofpardoprunox,anewpartialdopa-mineagonist,inearlyParkinson’sdisease.Mov Disord. 2010;25:730–8.

64. JonesCA,JohnstonLC,JacksonMK,etal.Aninvivopharmacologicalevaluationofpardoprunox(SLV308)—anoveldopamineD(2)/D(3)receptorpartialagonistand5-HT(1A)receptoragonistwithefficacyinexperimentalmodelsofParkinson’sdis-ease.Eur Neuropsychopharmacol. April29, 2010.Epubaheadofprint.

65. ContinuousapplicationoflisurideinParkinson’sdiseasebysubcutaneousinfusion.ClinicalTrials.govWebsite.Availableat:http://www.clinicaltrials.gov/ct2/show/NCT00408915?term=Parkinson%27s+disease+AND+phase+III&rank=53.AccessedJune7,2010.

66. BaroneP,LambJ,EllisA,etal.SumaniroleversusplaceboorropinirolefortheadjunctivetreatmentofpatientswithadvancedParkinson’sdisease.Mov Disord.2007;22:483–9.

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11Highlights Newsletter: Recognizing the Early Signs of Parkinson Disease and Optimizing Patient Outcomes

Recognizing the Early Signs of Parkinson Disease and Optimizing Patient Outcomes HIGHLIGHTS

N E W S L E T T E R

CPE EXAMInstructions: The assessment questions printed below allow you to preview the online

CPE exam. Please review all of your answers to be sure you have marked the proper letter on the online CPE exam. There is only one correct answer to each question.

1. Motor symptoms of PD

become apparent:

D�� Approximately 6 years

before nonmotor symptoms

develop.

E��After an estimated 70%

to 80% of dopaminergic

neurons are lost.

F�� In parallel with nonmotor

symptoms, because both are

tied to loss of dopaminergic

neurons.

G��Before deterioration of

dopaminergic neurons in the

substantia nigra.

2. A pharmacist should

evaluate further for PD by

asking about other early PD

symptoms in a patient who

presents with:

a. Rapid eye movement sleep

behavior disorder.

b. Urinary retention.

c. Hallucinations.

d. Headache.

3. Tremor is more likely to be

a symptom of PD than of

essential tremor in a patient

whose tremor:

a. Has a bilateral presentation.

b. Is more prominent when the

patient is still or at rest.

c. Is the only symptom.

d. Does not respond to

carbidopa/levodopa.

4. Which of these PD therapies

is a dopamine precursor that

is converted to dopamine in

the brain?

D� 3UDPLSH[ROH��

E� 6HOHJLOLQH�

F� $PDQWDGLQH�

G� /HYRGRSD�

5. Which of the following

investigational therapies

is being developed as

monotherapy for early PD,

among other uses?

a. Safi namide.

b. Sumanirole.

c. Pardoprunox.

d. Lisuride.

6. Which of the following

clinical trial designs has

been used to evaluate disease

modification in PD?

a. Proof-of-concept design.

b. Factorial design.

c. Crossover design.

d. Washout design.

7. Which of the following PD

therapies showed evidence

of disease modification when

used at its FDA-approved

dose in two delayed-start

trials of early PD?

a. Pramipexole.

b. Ropinirole.

c. Rasagiline.

d. Selegiline.

8. Neuroimaging trials suggest

a faster rate of decline in

dopaminergic activity in the

nigrostriatum with:

a. Ropinirole versus levodopa.

b. Pramipexole versus

levodopa.

c. Levodopa versus

pramipexole.

d. Selegiline versus levodopa.

9. A patient expresses interest in

using OTC supplements for

PD and asks if there is any

proof that they work. What

alternative therapy has been

shown in a randomized phase

III clinical trial to provide

neuroprotection in PD?

a. Vitamin E.

b. Coenzyme Q10.

c. Creatine.

d. To date, none have been

identifi ed.

10. The most effective therapy

for relief of characteristic

motor symptoms of PD is:

a. Carbidopa/levodopa.

b. A dopamine agonist.

c. An MAO-B inhibitor.

d. An anticholinergic agent.

11. Motor complications such as

dyskinesia, “on-off” episodes,

and wearing off effects occur

in many patients taking

which PD therapy long term?

a. Dopamine agonists.

b. MAO-B inhibitors.

c. COMT inhibitors.

d. Carbidopa/levodopa.

10-181 Parkinsons's Disease.indd 11 8/20/10 1:21 PM

American Pharmacists Association12

12. Leg edema is an adverse

effect of which of the following

PD therapies?

a. Carbidopa/levodopa.

b. Dopamine agonists.

c. Anticholinergic agents.

d. MAO-B inhibitors.

13. Both the “cheese reaction”

and serotonin syndrome

are most likely to occur in

patients taking:

D� &207�LQKLELWRUV�

E� 7KHUDSLHV�WKDW�LQKLELW�

0$2�W\SH�$��LQFOXGLQJ�

QRQVHOHFWLYH�0$2�

LQKLELWRUV�

F� 6HOHFWLYH�0$2�W\SH�%�

LQKLELWRUV�

G� &DUELGRSD�OHYRGRSD�

14. A patient with PD taking

carbidopa/levodopa complains

of nausea. Which represents

the best recommendation

to this patient for relief of

nausea?

D� ,QFUHDVH�À�XLG�LQWDNH�DQG�

GLHWDU\�¿�EHU�

E� 7DNH�WKH�FDUELGRSD�OHYRGRSD�

��KRXU�EHIRUH�HDWLQJ�

F� ,QFUHDVH�FDIIHLQH�LQWDNH�LI�

QRW�FRQWUDLQGLFDWHG�

G� ,QJHVW�JLQJHU�SURGXFWV��

15. A patient with PD develops

psychosis thereby making it

necessary to reduce the dose

and/or gradually discontinue

her PD medications. Which

of these agents should be

discontinued last?

D� &DUELGRSD�OHYRGRSD�

E� 'RSDPLQH�DJRQLVW�

F� $QWLFKROLQHUJLF�DJHQW�

G� 0$2�%�LQKLELWRU�

1. Go to Online CPE Quick List and click on the title of this activity.

2. Log in. APhA members enter your user name and password. Not an APhA member?

Just click “Create one now” to open an account. No fee is required to register.

3. Successfully complete the CPE exam and evaluation form to gain immediate access

to your Statement of Credit.

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from APhA Member Services at 800-237-APhA (2742) or e-mail

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