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Contributions of Dopaminergic Drugs and Disease Severity to Daytime Sleepiness in Parkinson Disease
Padraig E. O'Suilleabhain, MB;
Richard B. Dewey, Jr, MD
Arch Neurol. 2002;59:986-989.
ABSTRACT
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Background Excessive daytime somnolence is a common report among patients who have
Parkinson disease (PD). The relative contributions of disease severity and
of the various dopaminergic drugs are unclear.
Objective To separate and quantify the contributions of disease markers and drug
doses.
Methods Patients seen during a 7-month period at a center for movement disorders
completed the Epworth Sleepiness Scale. Treatment subgroups were compared.
The relationship to sedation of age; dopaminergic drug classes and doses;
Hoehn and Yahr stage; duration of disease; total score on the motor subsection
of the Unified Parkinson Disease Rating Scale; and the presence or absence
of dementia, depression, or hallucinations was calculated using simple and
multiple regression and t tests.
Results The Epworth Sleepiness Scale scores were higher among patients with
PD (mean [SD], 10.8 [5.3]; n = 368) compared with patients with other neurological
disorders (mean, 8.5 [5.1]; n = 243; P<.001).
A model containing the Hoehn and Yahr stage, levodopa dose, and use of a dopamine
agonist was the best at predicting the total score of Epworth Sleepiness Scale
in patients who have PD, but accounted for only 9% of the interindividual
variance. The parameter estimates (SE) corresponded to a 1.02 (0.03)–point
increase per Hoehn and Yahr stage, a 0.14 (0.06)–point increase per
100-mg increase in levodopa dose over 24 hours, and a 2.33 (0.57)-point increase
with use of an agonist. There was no statistically significant dose response
for agonists. No statistically significant difference in sedation among the
commonly used dopamine agonists was found.
Conclusions Somnolence in patients with PD, which is on average 25% higher than
in other neurological diseases, is related to PD stage, levodopa dose, and
the use of a dopamine agonist. However, most of the variability in sedation
levels in patients with PD as well as in controls is the result of, as yet,
unidentified factors.
INTRODUCTION
DAYTIME SOMNOLENCE in Parkinson disease (PD) has been recognized for
many years. Poorly restorative sleep and parkinsonian fatigue probably contribute
to daytime drowsiness, while some patients experience sedation as an adverse
effect of dopaminergic drugs. Occupational capacity and domestic quality of
life are clearly reduced when people feel groggy rather than alert. The prevalent
report of drowsiness in PD should probably be treated separately from the
uncommon "sleep attacks," a term introduced in 1999 to describe the unheralded
onset of sleep in potentially dangerous circumstances.1
Onset of sleep without prodromal sedation has been widely discussed since
then2-19
and is generally thought to be associated with the use of dopaminergic drugs,
more specifically with dopamine agonists. Herein we contribute our experience
with the less dangerous, but more common, problem of excessive drowsiness
in PD. In this article we try to separate and quantify the contributions of
disease markers and drug doses.
PATIENTS AND METHODS
We attempted to study all patients presenting to the Clinical Center
for Movement Disorders at the University of Texas Southwestern Medical School,
Dallas, between January 4, 2001, and July 24, 2001. The Epworth Sleepiness
Scale20 was distributed at check-in. The scale
consists of 8 questions about the likelihood of sleep under various conditions
in their daily life, and patients respond with scores of 0 (no chance of dozing)
to 3 (high chance of dozing); the sum of the 8 responses is reported as the
Epworth total. These data were entered into a database in which demographics,
drug information, and clinical notes are linked. For those patients seen more
than once during this period, the most recent visit was included in the study.
The equivalent dopamine agonist dose over 24 hours was calculated with
conversion factors of 1 mg of pergolide mesylate equals 1.5 mg of pramipexole
equals 10 mg of bromocriptine mesylate equals 5 mg of ropinirole hydrochloride.
The equivalent levodopa dose over 24 hours was calculated with conversion
factors of 75 mg of immediate-release levodopa equals 100 mg of controlled-release
levodopa. Tables generated using Microsoft Access (Microsoft Corp, Seattle,
Wash) queries were imported into SAS (SAS Inc, Cary, NC) for analysis. The
main outcome of interest was the Epworth total. The PD group and controls
were compared using t tests. The PD treatment groups
were analyzed with analysis of variance (ANOVA) (general linear model procedure)
with post hoc Scheffé test comparisons. Subgroups categorized by use
of a certain drug type or by the presence vs absence of dementia, depression,
or hallucinations were compared using t tests. Regression
analysis was performed for each of the continuous, interval, or ordinal independent
variables of interest: equivalent agonist dose, equivalent levodopa dose,
age, Hoehn and Yahr stage, disease duration, and Unified Parkinson Disease
Rating Scale (UPDRS) total. The best multiple regression model was selected
by stepwise adding variables in order of their significance in univariate
tests.
RESULTS
PATIENTS WITH PD COMPARED WITH CONTROLS
Seven hundred sixty-nine unique patients were seen in the clinic during
the study period, and Epworth data were available for 611. The study cohort
was composed of 368 patients with PD (94% of all patients with PD seen during
the study period) and 243 controls (65% of the patients without PD seen during
the study period).
The patients with PD had a mean (SD) age of 66.8 (10.3) years, and a
mean (SD) disease duration of 7.9 (6.0) years. The numbers at each Hoehn and
Yahr stage were as follows: 0, 1 patient; 1, 56 patients; 2, 144 patients;
2.5, 40 patients; 3, 80 patients; 4, 39 patients; and 5, 8 patients. The UPDRS
motor function (part III) scores, typically in the "on state"(ie, when the
individual is taking medication), were almost complete for 301 patients. By
"almost complete," we mean that either 24 or 25 of the 27 fields were filled:
in our database the action tremor fields are always omitted and the head tremor
field is commonly unreported. The mean (SD) UPDRS motor score was 23 (15)
points. Subjects were not systematically assessed for dementia, depression,
or hallucinations as part of the study protocol, but participants' notes were
searched for references to these problems. Dementia was noted in 33 patients,
active depression in 37, and hallucinations in 40.
The controls had other movement disorders (n = 191; most of these were
parkinsonian syndromes, essential tremor, or dystonia) or other neurological
problems (n = 52, of which the most common diagnoses in order were headaches,
dementia, neuropathy, and pain). Twenty-five of the controls were taking levodopa
and 8 were taking a dopamine agonist.
Mean (SD) Epworth total in patients with PD was 10.8 (5.3) points while
in the controls the mean was 8.5 (5.1) points (P<.001).
If the 33 controls taking a dopaminergic drug were omitted from consideration,
the control group mean was 8.0 (5) points.
SLEEPINESS IN PD AS A FUNCTION OF TREATMENT CLASS
Of the patients with PD, 18 were untreated and 350 were taking medications
for PD. Treatment was with levodopa monotherapy (n = 106), dopamine agonist
monotherapy (n = 57), or combined agonist-levodopa therapy (n = 187).
The distribution of Epworth totals for each PD treatment group is shown
in Figure 1. Combination therapy,
levodopa monotherapy, agonist monotherapy, and the nontreated groups had mean
(SD) scores of 11.8 (5.2) points, 9.9 (5.4) points, 10.1 (5.3) points, and
8.2 (4.3) points, respectively (F3,364 = 5.27, P<.001). Post hoc comparisons showed that the combination group
had higher scores than the levodopa or untreated groups. The mean (SD) ages
of the 4 treatment groups were different: 67 (9.7), 72 (8.6), 58 (9.3), and
65 (8.7) years, respectively (F3,364 = 29, P<.001) as were UPDRS motor scores: 21 (13) points, 30 (16) points,
15 (11) points, and 22 (19) points, respectively (F3,297 = 12.3, P<.001). When these 2 variables were included with the
treatment group as independent variables, the ANOVA model was again significant
(F5,295 = 3, P = .01), with the UPDRS
motor score (P = .01) and treatment group (P = .01) as significant predictors.
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Frequency histogram showing the number of patients with Parkinson
disease (PD) in each treatment group reporting the Epworth Sleepiness Scale
total score at each level, ie, 0 (no chance of dozing) through 24 (high chance
of dozing in all 8 situations).
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Analysis of covariance comparing Epworth totals between the dopamine
agonists when controlling for levodopa dose did not reveal a difference among
the agonists. There was a trend toward a higher Epworth total for those using
pergolide (least squares method mean estimate, 12.8, n = 71) and pramipexole
(12.2, n = 107) compared with ropinirole (10.6, n = 62) or bromocriptine (8.0,
n = 4). If the least commonly used agonist was omitted, the agonist drugs
again failed to show a significant difference.
RELATIONSHIP TO SLEEPINESS OF DRUG DOSE AND PD SEVERITY
Univariate linear regression models of Epworth total based on levodopa
dose, Hoehn and Yahr stage, and disease duration were significant (Table 1, "Simple Regression" section).
The UPDRS motor score showed a trend, while agonist dose and age did not reach
significance. If dose analyses were restricted to monotherapy groups, then
again the levodopa dose reached significance as a predictor (P = .04, n = 106) and the agonist dose did not (P = .80, n = 57).
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Factors Potentially Predictive of an Epworth Sleepiness Scale Total
Score in Patients With Parkinson Disease*
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The t tests showed that Epworth totals were
higher in patients using levodopa therapy than in those not taking levodopa,
and were also higher in those using compared with those not using dopamine
agonists (Table 1, "t Test" section). Epworth totals were no higher in patients with PD
who have dementia, depression, or hallucinations compared with subjects without
these comorbidities.
The best fit multiple regression model identified (F3,364
= 12.27, P<.001) combined levodopa dose and Hoehn
and Yahr stage, with agonist use as a dummy variable. The parameter estimates
and SEs of the estimates are listed in Table 1 ("Multiple Regression" section). The sum of squares attributed
to these variables was 9% of the total sum of squares.
Levodopa dose was correlated with Hoehn and Yahr stage (r293 = 0.35, P<.001) and with
UPDRS motor score (r253 = 0.33, P<.001): the dose increased with each increase in Hoehn
and Yahr stage, from 5.1 at stage 1 to 11.8 at stage 5. To control for collinearity
of disease severity and levodopa dose, the largest subgroup by Hoehn and Yahr
stage of levodopa-treated patients was reexamined. The Epworth total was regressed
using the levodopa dose, again with agonist use as a dummy variable. For patients
at stage 2, an increased Epworth total was almost associated with increased
dose (P = .06, n = 105). In the same manner, the
significance of the Hoehn and Yahr stage was analyzed among the largest subgroup
by similar levodopa dose. The Hoehn and Yahr stage was predictive of the Epworth
total (P = .04, n = 83) among patients taking 450-
to 600-mg levodopa equivalents over 24 hours.
COMMENT
Patients with PD were sleepier than our control patients, supporting
the perception that there are additional sedating factors in PD above and
beyond those in other neurological disease. However, with mean scores about
only 25% higher, the patients with PD were not that much sleepier than the
controls, and there was a broad area of overlap of their distributions. Untreated
patients with (early-stage) PD had Epworth scores similar to controls. Based
on their parameter estimates, 3 factors (levodopa dose, use of an agonist,
and PD severity) could account for most of the extra 2.3 points of sedation
experienced by the average patient with PD compared with the average neurological
control.
These 3 factors also predict to some degree sedation levels within the
PD cohort. While the predictors are correlated, combined models and subset
analyses suggest that drugs and disease each contribute to somnolence. In
agreement with our data, a statistically significant association between sedation
and increasing doses of levodopa was recently reported.19
We quantified this effect and found it to be small. An increment of 7 tablets
of immediate-release 25 mg of carbidopa/100 mg of levodopa per day worsened
the Epworth total by approximately 1 point. This may be an underestimation
owing to probable bias against those subjects with particular sensitivity
to sedation from levodopa therapy, as they are likely to remain at lower doses
to avoid this adverse effect. A dose effect was not identifiable for dopamine
agonists, but use of an agonist at any dose was associated with an increase
of more than 2 points in the Epworth total. We do not know whether the discrepancy
between the graded effect of levodopa and the all-or-nothing effect of dopamine
agonists reflects a biological difference in their mode of action or is merely
a statistical fluke. An association between nocturnal sleep disruption and
disease severity has also been previously reported.10
In our study, an association between daytime somnolence and parkinsonism was
more striking when the Hoehn and Yahr stage was used as the measure of disease
severity, arguably because the Hoehn and Yahr stage better represents disease
burden than the on-state UPDRS total. How disease burden might contribute
to sedation is unclear. The relationship may be indirect, for example, from
nocturnal rigidity or nocturia disrupting sleep, or perhaps could be due to
progressive degeneration of brainstem arousal neurons.
Notwithstanding the contributions of dopaminergic drugs and disease
severity to somnolence in PD, the important point remains that these factors
account for only 9% of the interindividual variability in the Epworth total.
As yet unidentified factors are needed to explain most of the variability.
The unidentified factors may be similar in PD to those in other neurological
diseases, as the variability in our PD and control groups was about the same.
The Epworth Sleepiness Scale was developed as a measure of the tendency
to doze off.20 We believe this scale has face
validity as a measure of drowsiness. It is our impression that this drowsiness
is a common chronic problem in PD for which there is no validated measure.
Not to be confused with this problem, a public health concern has also been
raised about the uncommon phenomenon of sudden-onset sleep in PD. Others have
used the Epworth Sleepiness Scale to categorize patients as higher risk vs
lower risk of sudden onset of sleep. In a study focused on this problem, Hobson
et al12 recently reported that just over half
of their patients with PD suffered excessive daytime sleepiness using a cutoff
point Epworth total of 7. If we use the same standard, an even larger fraction
of our patients would be classified as excessively sleepy. However, it might
be argued that this threshold is too low to be meaningful, as most neurological
patients with PD and controls have elevated scores by this standard. For those
clinicians who use an Epworth score in deciding whether to advise against
driving, we would caution against using too low a threshold and against using
this standard more restrictively in patients with PD compared with other clinic
patients, as no more than anecdotal evidence exists that patients with PD
above that threshold are at a sufficiently higher risk of sudden-onset sleep
than neurological patients in whom driving is not restricted. In addition,
we suggest there is, as yet, insufficient rationale for dichotomizing patients
with PD into normal vs sedated using any particular cutoff point, as Epworth
totals have a reasonably bell-shaped distribution (Figure 1). Instead, a clinician recording an Epworth score can locate
that patient's sedation along a spread, based on a mean and SD derived either
locally or from a published cohort such as ours.
How has this elevated awareness of sedation, and the results of our
analysis, affected our practice? We now ask all our patients about daytime
somnolence. In the few patients with a clear temporal relationship between
drug dosing and sedation, we reduce or change the offending drug. We compromise
motor control by reducing dopaminergic drugs only among the subset of patients
with intolerance to all agents as demonstrated by sedation on challenge and
rechallenge. However, because levodopa therapy contributes modestly to the
problem for the average patient with PD, we pay more attention to other drugs
that may have sedative adverse effects, and to nocturnal sleep patterns. If
sleep is poor because of reemergent immobility or stiffness, or because of
rapid eye movement sleep behavioral disorder, we try to address these matters
of treatment with nocturnal levodopa and clonazepam, respectively. We consider
off-label use of modafinil for those patients without another solution to
disabling somnolence.21-22 Counseling
patients and their relatives about the safety risks of driving or operating
heavy machinery when sedated is offered when appropriate. For those rare patients
with a history of sudden-onset sleep, these risks are particularly emphasized.
AUTHOR INFORMATION
Accepted for publication February 11, 2002.
Author contributions: Study concept and design (Dr Dewey); acquisition of data (Drs
O'Suilleabhain and Dewey); analysis and interpretation of data (Drs O'Suilleabhain and Dewey); drafting of the manuscript (Drs O'Suilleabhain and Dewey); critical revision of the
manuscript for important intellectual content (Drs O'Suilleabhain
and Dewey); statistical expertise (Dr O'Suilleabhain); administrative, technical, and material support (Dr Dewey); study supervision (Dr Dewey).
Corresponding author and reprints: Padraig E. O'Suilleabhain, MB,
5323 Harry Hines Blvd, Dallas, TX 75390-9036 (e-mail: padraig.osuilleabhain{at}UTSouthwestern.edu).
From the Clinical Center for Movement Disorders, Department of Neurology,
University of Texas Southwestern Medical School, Dallas.
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