Reviews

Translated from Rev Prescrire April 2015; 35 (378): 286-288

Parkinsons disease:
initial treatment of motor
disorders
Key points

Parkinsons disease is character-

ised by three main symptoms: slowness and paucity of movements,

rigidity, and resting tremor. Rapid
improvement in these symptoms
after levodopa administration supports the diagnosis of Parkinsons
disease.

It is important to inform the patient

tactfully, allowing him or her to control the pace at which information on
the diagnosis, symptoms and prognosis is conveyed.

arkinsons disease is a central

nervous system disorder char
acterised by motor impairment
and various other signs and symp
toms, including neuropsychiatric
disorders (1).
The principal motor disorders are
due to gradual degeneration of dopa
minergic neurons in the brain that
are involved in carrying out move
ments. This disrupts the physiologic
al balance between dopaminergic
and cholinergic neurons, the latter
becoming dominant (2,3).
In Europe, the estimated preva
lence of Parkinsons disease is about
1.5% among persons over 65 years
of age and 3.5% among those over
85. Parkinsons disease rarely occurs
before age 40 (1,4,5).

Previously untreated patients with

marked functional impairment should
receive medication. The choice is
essentially between levodopa and
ropinirole, and mainly depends on
the patients age.

walking, and difficulty in perform

ing activities of daily living;
Rigidity, manifested by resistance
to passive limb extension, which
occurs in successive jerks (cog
wheel rigidity);
Slow resting tremor occurring on
muscle relaxation (1-3).
Tremor is inconsistent in early Par
kinsons disease. It is sometimes felt
by the patient but not visible to an
observer. Symptoms are often uni
lateral, typically on the same side as
the tremor (1-3).
A marked improvement in these
symptoms soon after starting treat
ment with levodopa supports the
diagnosis of Parkinsons dis
ease(2,6).
In early-stage Parkinsons disease,
other less specific manifestations
sometimes occur, including: disor
ders related to involvement of the
autonomic nervous system (includ
ing orthostatic hypotension, exces
sive salivation and constipation),
mood disorders (including depres
sion and apathy), sleep disorders,
pain, hallucinations or delusions.
These poorly specific symptoms are
sometimes present before the onset
of motor disorders (1,3,7).

Poorly known causes. Par

kinsons disease has no clear
ly identified cause, but genet
ic factors and brain injury might play
a role. Many toxicological and epide
miological data are consistent with a
link between pesticide exposure and
Parkinsons disease(3,5,8).
Certain medications.
Some drugs can worsen the
symptoms of Parkinsons dis
ease, thus reducing treatment effica
cy. Other drugs can cause or exacer
bate parkinsonian syndromes,
mainly neuroleptics: antipsychotics
or hidden neuroleptics used as
antiallergic or antiemetic medica
tion, or for migraine or sleep disor
ders. Other drugs may also be
involved: 5-HT3-receptor antagonist
(setrons), antidepressants, buspirone,
trimetazidine, cholinesterase inhibi
tors used in Alzheimers disease, cal
cium channel blockers, valproic
acid(4).
Inform patients and preserve their independence.
The diagnosis of Parkinsons
disease must be conveyed tactfully
to the patient and family, taking into
account their prior knowledge of the
disease and their emotional reaction.
The patient should first be informed
of his or her existing symptoms, and
then be allowed to control the pace
at which information is communi
cated on the somewhat unpredict
able course of the disease and avail
able therapeutic options. The
existence of support groups should
be highlighted.

A triad of motor symptoms. Diagnosis of Parkin

sons disease is based primar
ily on clinical signs, especially three
motor disorders which may be more
or less severe:
Slowness and paucity of move
ment (bradykinesia and hypokine
sia), resulting in a loss of facial
expression, loss of arm swing when

Patients with minimal discomfort

or mild disability derive little benefit
from drug therapy. Physiotherapy
and physical exercises are sometimes useful.

Not to be confused with

other central nervous system disorders. The tremor
associated with Parkinsons disease
must be distinguished from other
disorders, including: essential trem
or, which is often familial and occurs
during activities such as writing or
eating; some borderline motor defi
cits; Lewy body dementia; and
sequelae of encephalitis, etc. Balance
and gait disorders are often present
in advanced-stage Parkinsons dis
ease, but their early onset is sugges
tive of another disease (1,3,6).

P rescrire I nternational September 2015/Volume 24 N 163 Page 215

Reviews Parkinsons disease: initial treatment of motor disorders

Drugs to avoid for initial treatment
of Parkinsons disease
Amantadine. Amantadine is a weak dopamine agonist, which also has antimuscarinic effects. It has no proven efficacy when used as single-agent first-line therapy in
Parkinsons disease (2,4).
Monoamine oxidase type B (MAO-B) inhibitors. MAO-B inhibitors (rasagiline,
selegiline) have only a modest impact on motor symptoms of Parkinsons disease,
barely postponing the need for levodopa. When used early in the disease, serious
adverse effects that are disproportionate to the drugs limited efficacy include: psychiatric disorders, cardiac arrhythmia, stroke and myocardial infarction, as well as a possible
increase in mortality. MAO-B inhibitors also increase the risk of hypertensive crises
associated with levodopa (2,4).
Rotigotine. Rotigotine is a non-ergot dopamine agonist available only in transdermal
patch form. Rotigotine seems less effective than ropinirole in Parkinsons disease; it also
has many systemic adverse effects, as well as patch application site reactions (17).
Levodopa + entacapone. When used as first-line treatment for Parkinsons disease,
the combination of levodopa + entacapone, a catechol-O-methyltransferase (COMT)
inhibitor, is barely more effective than levodopa alone but causes more nausea, diarrhoea
and dyskinesia, which occur earlier and more frequently (2).
Prescrire

There is no cure or treatment

capable of slowing the progression of
Parkinsons disease. Treatment is
aimed at attenuating symptoms and
preserving the patients indepen
dence for as long as possible. The
optimal timing of treatment initia
tion is controversial (2,3,9).

Physiotherapy and adapted exercises. Patients with

minimal discomfort or mild
disability derive little benefit from
drug therapy (3).
There is some weak evidence that
physical therapy or adapted exercise
programmes (brisk walking, swim
ming, etc.) may have a favourable
effect on motor disorders and quali
ty of life. The value of speech thera
py for improving articulation is
uncertain (2,10).
Drug therapy for marked
functional impairment.
Patients with previously
untreated Parkinsons disease should
be offered drug therapy when the
functional impairment becomes
incapacitating. Current treatments
are designed to enhance dopaminer
gic activity, either with levodopa (a
dopamine precursor), or with a
non-ergot derivative dopamine ago
nist such as ropinirole (2,3).

Levodopa: rapidly effective on signs and symptoms, but causes lateonset motor disorders. Levodopa is
the most effective drug for treatment
of the motor symptoms of Parkin
sons disease. It increases speed of
movements and reduces both stiff
ness and, to a lesser degree, tremor.
All patients with Parkinsons disease
initially respond to levodopa and
experience an improvement in qual
ity of life. After several years of
levodopa therapy, however, some
patients develop motor fluctuations
and dyskinesia (2,11,12).
Levodopa is administered as a fixeddose combination with a dopa-decar
boxylase inhibitor such as carbidopa
or benserazide, as this allows lower
doses of levodopa to be used and
reduces peripheral gastrointestinal
and cardiac adverse effects(2,13).
Levodopa is introduced gradually,
without seeking immediate or com
plete control of all symptoms. The
dose is adapted to the clinical
response, and the lowest effective
dose should be used (3).
The levodopa + peripheral dopadecarboxylase inhibitor combination
is more manageable in immediate-
release form than in extended-
release form (14).
The adverse effect profile of levodopa mainly consists of: gastrointestinal
disorders (including nausea); ortho
static hypotension and, sometimes,

Page 216 P rescrire I nternational September 2015/Volume 24 N 163

hypertensive crises; psychiatric

d isorders, including compulsive

behaviours; daytime drowsiness

(sometimes of sudden onset); abnor
mal movements; and closed-angle
glaucoma (4).
Levodopa should be taken with a
meal or snack to reduce nausea (9).
Drugs that decrease the effects of
levodopa include spiramycin, iron, vitamin B6 and phenytoin (4).
There is no evidence that adding a
dopamine agonist to levodopa early
during treatment improves motor
symptoms (2).
Ropinirole: for younger
patients. Ropinirole, a
non-ergot derivative dopa
mine agonist, is less effective than
levodopa in improving motor disor
ders but results in fewer motor fluc
tuations in the long term. Treatment
may be started with ropinirole to
delay the need for levodopa therapy
and thus postpone its adverse motor
effects; this choice of initial treat
ment seems appropriate for patients
under 65, keeping levodopa in
reserve(a)(2,9).
The adverse effect profile of dopa
mine agonists mainly consists of: gas
trointestinal disorders; hypotension
(including postural hypotension);
psychiatric disorders (including com
pulsive behaviours; see next section);
and daytime drowsiness, sometimes
of sudden onset. Unlike ergot dopa
mine agonists, ropinirole does not
cause retroperitoneal or pleuropul
monary fibrosis, heart valve disease,
or vasoconstriction(4).
Ropinirole interacts with drugs that
inhibit cytochrome P450 isoenzyme
CYP 1A2, including fluoroquinolo
nes and macrolides (4).
Watch out for behavioural
disorders with dopamin
ergic drugs. Various com
pulsive behaviours have been
reported with dopaminergic drugs,
including compulsive buying or
shopping, overeating and bulimia,
pathological gambling, hypersexual
ity (including exhibitionism, paedo
philia and zoophilia), that can have
major familial, social or legal reper
cussions. It is important to inform
patients and their families or carers
of these risks (15,16).
Prescrire

a- Mid 2015 provisional results of a pragmatic randomised trial showed that levodopa was sligthly more
effective than dopamine agonists on motor disorders, with
more cases of dyskinesia but less neuropsychiatric and
gastrointestinal reactions. In young patients the advantage of using a dopamine agonist first is uncertain(Rev
Prescrire 2015; 35 (383): 690-691, to be translated in a
coming issue).

Literature search and methodology

This review was based on data published in la
revue Prescrire up to issue 374 (December 2014)
and in the Prescrire Drug Interactions Guide. Additional sources included the clinical pharmacology
textbook Martindale The Complete Drug Reference
(www.medicinescomplete.com) and the internal
medicine website UpToDate (www.up todate.com),
accessed up to 15 November 2014.
This review was prepared using the standard
Prescrire methodology, which includes verification
of the choice of documents and their analysis, and
multiple quality controls.

1-Chou KL et al. Clinical manifestations of Par

kinson disease UpToDate 2014.
2-Prescrire Rdaction Traitement de la maladie
de Parkinson. Premire partie. Dabord une
monothrapie par lvodopa ou agoniste dopami
nergique Rev Prescrire 2011; 31 (329): 200-205.
3-Prescrire Editorial Staff Treatment of Parkin
sons disease Prescrire Int 1993; 2 (5): 36-39.
4- Prescrire Rdaction 12-4. Patients parkin
soniens, 19-1-3. Profil deffets indsirables des
neuroleptiques, Fiche P1c. Inhibiteurs et sub
strats de lisoenzyme CYP 1A2 du cytochrome
P450 Rev Prescrire 2014; 34 (374 suppl. interac
tions mdicamenteuses).
5-Jankovic J et al. Etiology and pathogenesis of
Parkinson disease UpToDate 2014.
6-Chou KL et al. Diagnosis of Parkinson disease
UpToDate 2014.
7- Prescrire Editorial Staff Treatment of Parkin
sons disease. Psychological disorders: striking a
balance in order to optimise antiparkinsonian
treatment Prescrire Int 2011; 20 (120): 242-245.
8- Prescrire Rdaction Pesticides et maladie de
Parkinson Rev Prescrire 2013; 33 (362): 943.
9-Tarsy D et al. Pharmacologic treatment of Par
kinson disease UpToDate 2014.

10- Tarsy D et al. Nonpharmacologic management

of Parkinson disease UpToDate 2014.
11-Prescrire Editorial Staff Pergolide and Parkin
sons disease: no clear benefit Prescrire Int 2000; 9
(50): 177-179.
12- Prescrire Rdaction Lvodopa et inhibiteur de
la dopa-dcarboxylase Rev Prescrire 1989; 9 (88):
339.
13- Prescrire Editorial Staff Levodopa/carbidopa
controlled-release tablets Prescrire Int 1994; 3 (12):
99-101.
14- Prescrire Rdaction Traitement de la maladie
de Parkinson. Deuxime partie. Rduire les fluc
tuations motrices sous lvodopa Rev Prescrire
2011; 31 (330): 273-279.
15- Prescrire Rdaction RCP des mdicaments
dopaminergiques toffs: risques de troubles com
pulsifs Rev Prescrire 2013; 33 (354): 259.
16-Prescrire Editorial Staff Dopamine agonists:
pathological gambling and hypersexuality Pres
crire Int 2008; 17 (97): 200-201.
17- Prescrire Editorial Staff Rotigotine. Parkin
sons disease: a step backward Prescrire Int 2008;
17 (94): 60.

Translated from Rev Prescrire April 2015; 35 (378): 282-285

Prevention of deep vein thrombosis

First choice treatments

eep vein thrombosis is due to

the formation of a blood clot in
a deep vein, usually in a lower
limb. Migration of all or part of the clot
into a pulmonary artery can result in
pulmonary embolism, which can be
fatal despite treatment(1,2).
Prevention of pulmonary embo
lism is based on prophylaxis of deep
vein thrombosis in at-risk situations,
treatment of confirmed venous
thrombosis, and prevention of cardi
ac embolism (3). The following arti
cle focuses solely on the prevention
of deep vein thrombosis.

Drugs can also increase

the risk of thromboembol
ism. The following drugs are
associated with an increased risk of
deep vein thrombosis:
Oestroprogestogens, particularly
those containing a third-generation
progestogen (desogestrel or gestodene)
or drospirenone, and transdermal
patches containing norelgestromin;
Anti-oestrogens such as tamoxifen
and raloxifene;
Aromatase inhibitors;
Cytotoxic drugs;
Neuroleptics;
Strontium;
Corticosteroids and nonsteroidal
anti-inflammatory drugs;
Tranexamic acid (6).
Identifying high-risk
s ituations. The risk of
venous thrombosis is partic
ularly high after trauma or surgery
requiring prolonged immobilisation,
and in patients with certain medical

conditions; these situations warrant

prophylaxis provided the bleeding
risk is acceptable (7).
The risk of thrombosis is particular
ly high following: hip fracture sur
gery; spinal trauma with spinal cord
injury; multiple severe trauma; hip or
knee replacement surgery; major
abdominal or pelvic surgery; myocar
dial infarction treated without throm
bolysis; and stroke resulting in pro
longed immobilisation. Other
high-risk situations warranting anti
thrombotic prophylaxis include treat
ment with cytotoxic drugs or with
oestrogen antagonists in the postop
erative period, and hospitalisation in
an intensive care unit(4,8,9).
Prophylaxis is also warranted in
situations generally associated with a
less elevated risk of venous thrombosis
if the patient has other risk factors such
as advanced age, a personal or family
history of thrombosis, dehydration,
cancer, obesity, acute infection, and an
exacerbation of cardiac or respiratory
failure. These situations include: pro
longed bed rest; the period after
lengthy laparoscopic or arthroscopic
surgery; gynaecological, urological or
thoracic surgery; and neurosur
gery(2,4,8,10-12).

Specific contexts and

contributory factors.
Deep vein thrombosis and
pulmonary embolism often occur in
specific situations such as surgery,
cancer, bone or spinal trauma,
cardiovascular events, prolonged

immobilisation, kidney disease, and

pregnancy (including the post
partum period)(3-5).
Several individual factors can
increase the risk of deep vein
thrombosis, including a personal
or family history of deep vein
thrombosis, advanced age, obesity,

diabetes, heart failure, inflamma

tory bowel disease and thrombo
philia (3,5).

P rescrire I nternational September 2015/Volume 24 N 163 Page 217

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