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Nonsteroidal antiinflammatory drug use and the risk for Parkinson's disease.

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Nonsteroidal
Antiinflammatory Drug Use
and the Risk for Parkinson’s
Disease
Honglei Chen, MD, PhD1,2 Eric Jacobs, PhD3
Michael A. Schwarzschild, MD, PhD4
Marjorie L. McCullough, ScD3 Eugenia E. Calle, PhD3
Michael J. Thun, MD3 and Alberto Ascherio, MD, DrPH2,5
We investigated whether nonsteroidal antiinflammatory
drug use was associated with a lower risk for Parkinson’s
disease (PD) in a large cohort of US men and women.
PD risk was lower among ibuprofen users than nonusers.
Compared with nonusers, the relative risks were 0.73 for
users of fewer than 2 tablets/week, 0.72 for 2 to 6.9 tablets/week, and 0.62 for 1 or more tablets/day (p trend ⴝ
0.03). No association was found between the use of aspirin, other nonsteroidal antiinflammatory drugs, or acetaminophen and PD risk. The results suggest that ibuprofen use may delay or prevent the onset of PD.
Ann Neurol 2005;58:963–967
Evidence from both experimental and postmortem
studies suggests a role of neuroinflammation in the
pathogenesis of Parkinson’s disease (PD).1,2 Consistently, protective effects of nonsteroidal antiinflammatory drugs (NSAIDs) have been observed in animal
models of PD.3–5 We have reported previously that
nonaspirin NSAID use was associated with a lower risk
for PD.6 Here, by taking advantage of the wellestablished American Cancer Society’s Cancer Prevention Study II (CPS-II) Nutrition Cohort, we were able
to further examine the relation between NSAID use
and PD risk with more detailed information on different types of NSAIDs.
From the 1Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle
Park, NC; 2Department of Nutrition, Harvard School of Public
Health, Boston, MA; 3Epidemiology and Surveillance Research Department, American Cancer Society, Atlanta, GA; 4Department of
Neurology, Massachusetts General Hospital; and 5Department of
Epidemiology, Harvard School of Public Health, Boston, MA.
Received Mar 21, 2005, and in revised form Jun 2 and Aug 8.
Accepted for publication Aug 8, 2005.
Published online Oct 20, 2005, in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.20682
Address correspondence to Dr Ascherio, Department of Nutrition,
Harvard School of Public Health, 665 Huntington Avenue, Boston,
MA 02115. E-mail aascheri@hsph.harvard.edu
© 2005 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
963
Subjects and Methods
Study Population
The Cancer Prevention Study II Nutrition Cohort is a prospective study of 86,404 men and 97,786 women that was
initiated in 1992 to investigate risk factors for cancer.7 Participants were drawn from a cohort of over 1 million people who
replied to a mailed survey in 1982. In 1992, participants answered a detailed questionnaire that included questions on
four types of commonly used analgesics. Follow-up surveys
were conducted in 1997, 1999, and 2001. In the 2001 survey,
a specific question on the lifetime occurrence of PD was asked.
Of the 147,795 participants who completed the 2001 questionnaire, 146,948 (99.4%; 65,657 men and 81,291 women)
were included after excluding those with missing or inconsistent information on the use of analgesics in 1992 and 1997
(n ⫽ 667) or those with PD at baseline (n ⫽ 180). Follow-up
started on the date of return of the 1992 questionnaire and
ended on the date when the first symptoms of PD were noticed for PD cases or September 30, 2001, for participants
without PD. The study was approved by the Human Subject
Committee at Harvard School of Public Health and the Institutional Review Board at Emory University.
Case Ascertainment
The case ascertainment procedures were similar to those we
used in our previous studies. In brief, a case was confirmed if
the diagnosis was considered clinically definite or probable
by the treating neurologist, or if the medical record included
either a final diagnosis of PD made by a neurologist or evidence at a neurological examination of at least two of the
four cardinal signs with one being rest tremor or bradykinesia, a progressive course, and the absence of unresponsiveness
to L-dopa or other features suggesting an alternative diagnosis. Of the 413 PD cases included in this analysis, 67.6% of
the diagnoses were confirmed by the treating neurologists
(55.0%) or movement disorder specialists (12.6%), 21.1%
by review of the medical records, and 11.4% by the treating
internists or family physicians.
Assessment of Nonsteroidal Antiinflammatory
Drug Use
In the 1992 questionnaire, participants were asked whether
they took each of the following analgesics regularly during
the past year: aspirin, acetaminophen, ibuprofen, or other
nonsteroidal analgesics. Users were further asked, on average,
how many days per month they took each drug, how many
tablets they took per day, and the duration of use. NSAID
use was updated in 1997. The 1997 survey asked separately
about “baby or low dosage aspirin” and “regular or extra
strength aspirin”; we counted four tablets of baby aspirin as
one regular tablet in 1997.
started or stopped analgesic use between 1992 and 1997. We
calculated the relative risks (RRs) and 95% confidence intervals adjusted for age and sex with the Mantel–Haenszel
method.9 The RRs with further adjustment for smoking status (never, past, or current; the current smoker group was
further divided based on consumption: 1–14 and ⱖ15 cigarettes/day) were derived from Cox proportional hazard models. Further adjustments for baseline supplemental use of vitamin C, vitamin E, or multivitamin, coffee consumption
(1982 only), and arthritis (1982 only), or for other analgesic
use did not change risk estimates.
Finally, we pooled the results for nonaspirin NSAIDs with
our previous results from the Health Professionals Follow-up
Study (HPFS) and the Nurses Health Study (NHS).6 For
this purpose, we combined ibuprofen use with that of other
NSAIDs, because ibuprofen use was not asked separately in
the previous study. Statistical testing showed no heterogeneity among the risk estimates from different cohorts. The
summary RR thus was obtained with a fixed-effects model by
averaging the natural logarithms of the RRs from individual
studies weighted by the inverses of their variances.
Results
Baseline population characteristics are presented in Table 1. During 1,254,165 person-years of follow-up, a
total of 413 incident PD cases were identified. A significant inverse association ( p trend ⫽ 0.03) was suggested between the cumulative updated dosage of ibuprofen use and PD risk (Table 2). Similar results were
obtained in sensitivity analyses by excluding the first 2
years of follow-up, excluding diagnoses by internists, or
censoring follow-up at age 75 years. Duration of ibuprofen use reported at baseline was not significantly related to PD risk: compared with nonusers, the RR was
0.78 for those with fewer than 2 years of use, 0.79 for
2 to 4.9 years, and 0.72 for 5 or more years ( p
trend ⫽ 0.2). Overall, ibuprofen users had a lower PD
risk than nonusers (RR, 0.65; 95% confidence interval,
0.48 – 0.89; p ⫽ 0.007). Similar RRs were obtained in
subgroup analyses stratified by sex, age, or smoking status. Unlike ibuprofen, the use of aspirin, other
NSAIDs, or acetaminophen was not associated with
PD risk.
The RR comparing users of nonaspirin NSAIDs
(ibuprofen and other nonaspirin NSAIDs) with nonusers was 0.78 (95% confidence interval, 0.60 –1.02).
When pooled with the results from our previous
study,6 nonaspirin NSAID users had a 26% lower risk
than nonusers (Fig).
Statistical Analyses
For each drug, we defined participants as users or nonusers.
Users were further categorized according to dosage as follows: fewer than 2 tablets/week; 2 to 6.9 tablets/week; and 1
or more tablets/day. We used a time-dependent variable (cumulative updated dosage8) for use of each analgesic to take
advantage of the updated information collected in 1997. For
duration analyses, only baseline information was analyzed because it was impossible to estimate duration for those who
964
Annals of Neurology
Vol 58
No 6
December 2005
Discussion
Results from this study are consistent with our previous findings that users of nonaspirin NSAIDs, but not
aspirin, had a lower risk for PD than nonusers.6 Importantly, this study further suggests that only certain
nonaspirin NSAIDs such as ibuprofen reduce the risk
for PD.
Table 1. Population Characteristics according to the Use of Different Types of NSAIDs and Acetaminophen at Baseline (1992)a
Aspirin
Ibuprofen
Users
Nonusers
Other NSAIDs
Users
Characteristic
Nonusers
Nb
Age (mean, yr)
Male (%)
Current smokers (%)
Past smokers (%)
Coffee drinkers ⬍1/day (%)c
Coffee drinkers ⱖ1/day (%)c
Arthritis (%)c
Supplement use (%)
Vitamin E
Vitamin C
Multivitamin
NSAID users in 1992 (%)
Aspirin
Ibuprofen
Other NSAIDs
Acetaminophen
NSAID users in 1997 (%)
Aspirin
Ibuprofen
Other NSAIDs
Acetaminophen
76,877
62.5
39.9
7.8
43.9
6.5
76.5
15.6
57,181
63.1
51.6
7.7
49.6
6.4
79.1
16.5
18.2
24.2
35.6
22.9
29.7
41.7
19.1
25.3
36.5
24.6
31.1
44.5
20.0
26.2
37.6
23.6
30.0
44.2
19.4
25.7
36.5
23.3
29.9
44.0
—
14.7
6.9
16.7
—
25.1
6.8
23.4
39.5
—
5.8
13.7
55.8
—
9.5
40.4
42.4
17.7
—
17.5
42.1
27.0
—
36.7
40.7
14.4
5.0
—
51.1
41.5
12.7
—
27.5
17.5
8.1
21.5
71.4
21.7
9.0
21.8
45.5
12.8
7.3
19.8
48.0
47.1
12.5
28.6
46.3
19.1
6.2
20.4
39.8
20.2
39.7
36.4
47.3
17.5
7.3
13.2
43.7
27.3
12.5
50.4
110,265
25,726
63.1
61.5
46.9
38.4
7.9
7.6
45.9
48.3
6.5
6.4
77.5
78.6
14.7
21.2
Nonusers
Users
Acetaminophen
129,367
9,338
62.8
62.9
45.9
33.7
7.9
6.6
46.3
47.2
6.4
7.1
77.8
76.5
14.2
37.7
Nonusers
Users
103,262
24,558
63.0
62.0
48.1
38.6
7.7
7.6
46.5
47.5
6.2
7.0
78.1
76.5
13.9
22.0
a
Means are presented for age; proportions are presented for all other variables after direct standardizations to the age distribution of the entire
cohort.
b
Number may not add up to total because of missing values.
c
Information from the 1982 questionnaire was used.
NSAID ⫽ nonsteroidal antiinflammatory drug.
NSAIDs are best known as inhibitors of proinflammatory cyclooxygenase (COX) enzymes.10 Laboratory
investigations show COX-2 upregulation in dopaminergic neurons in both PD patients and mouse models
of PD.11 Furthermore, in animal experiments, degeneration of dopaminergic neurons was attenuated with
the treatment of COX-2 inhibitors or the knockout of
COX-2 gene,11 supporting a possible role of the
COX-2 enzyme. Other studies suggest that NSAIDs
may also exert their neuroprotective effects by activating the nuclear factor peroxisome proliferator-activated
receptor ␥, scavenging hydroxyl radicals or nitric oxide,
or protecting against glutamate neurotoxicity.12–15
That only use of ibuprofen, but not of other
NSAIDs, was related to lower PD risk suggests that
some specific effects of ibuprofen may be important.
Ibuprofen increased the number of dopaminergic neurons in vitro and protected these neurons against glutamate neurotoxicity more so than aspirin or acetaminophen,16 and ibuprofen, but not naproxen, prevented
neuronal oxidative damage induced by intracerebral injection of lipopolysaccharide,17 which can cause selective degeneration of dopaminergic neurons via its inflammatory actions. Nevertheless, the relevance of these
observations to potential neuroprotective effects of ibuprofen in PD is uncertain.
A limitation of this study is that the participants
could not be physically examined by the investigators.
The classification of cases as definite or probable PD
therefore does not conform to the application of uniform criteria. Although a few misdiagnoses are inevitable, in recent large clinicopathological studies, the accuracy of the clinical diagnosis of PD made by
neurologists was found to be 90%.18 Bias from this
source is thus likely to be small. Furthermore, this bias
probably would have caused an underestimation of the
associations, because case identification was most likely
independent of NSAID use. This study included only
individuals who participated in the 2001 survey; there
could be a bias if death or losses to follow-up were
related to both NSAID use and risk for PD, which
appears unlikely. Selective mortality among ibuprofen
users with PD could also create a spurious finding, but
this would be inconsistent with the fact that identical
results were observed among younger participants for
whom mortality was low. Confounding by indication
is also unlikely because no condition that leads to ibuprofen use and also decreases PD risk has ever been
reported and controlling for arthritis in the analyses
made no difference to the risk estimates.6 Finally, the
information on type and dosage of NSAIDs used by
participants in this study was limited. We were there-
Chen et al: NSAID Use and PD Risk
965
Table 2. Relative Risks and 95% Confidence Intervals of Parkinson’s Disease according to the Dosage of Each Type of NSAIDs or
Acetaminophen (1992–2001)
RR (95% CI)
Person-Yearsa
Aspirin
Nonusers
⬍2/week
2–6.9/week
ⱖ1/day
p for trend
Ibuprofen
Nonusers
⬍2/week
2–6.9/week
ⱖ1/day
p for trend
Other NSAIDs
Nonusers
⬍2/week
2–6.9/week
ⱖ1/day
p for trend
Acetaminophen
Nonusers
⬍2/week
2–6.9/week
ⱖ1/day
p for trend
a
No. of Casesa
Age and Sex Adjusted
Further Adjusted for Smoking
612,919
140,578
187,445
232,043
184
45
87
83
1.0 (referent)
0.99 (0.71–1.37)
1.31 (1.01–1.69)
1.00 (0.78–1.30)
0.5
1.0 (referent)
1.01 (0.73–1.41)
1.34 (1.04–1.74)
1.01 (0.78–1.31)
0.8
922,112
111,078
76,039
81,635
339
27
17
16
1.0 (referent)
0.73 (0.49–1.08)
0.72 (0.44–1.16)
0.61 (0.37–1.01)
0.03
1.0 (referent)
0.73 (0.49–1.08)
0.72 (0.44–1.17)
0.62 (0.37–1.02)
0.03
1,100,906
27,190
24,046
55,753
367
8
8
17
1.0 (referent)
0.90 (0.45–1.82)
1.02 (0.51–2.06)
0.99 (0.61–1.60)
0.96
1.0 (referent)
0.91 (0.45–1.84)
1.01 (0.50–2.04)
0.98 (0.60–1.60)
0.95
872,656
130,495
76,973
60,163
304
40
22
18
1.0 (referent)
0.94 (0.67–1.30)
0.92 (0.60–1.42)
0.95 (0.59–1.54)
0.8
1.0 (referent)
0.93 (0.67–1.30)
0.93 (0.60–1.44)
0.97 (0.60–1.56)
0.8
Number may not add up to total because of missing values.
NSAID ⫽ nonsteroidal antiinflammatory drug; RR ⫽ relative risk; CI ⫽ confidence interval.
Fig. The relative risk (RR) and 95% confidence interval (CI) of Parkinson’s disease according to baseline use of nonaspirin nonsteroidal antiinflammatory drugs (NSAIDs) in the meta-analysis of all three cohorts. Rectangles indicate RRs from individual studies;
horizontal lines represent 95% CIs; unshaded diamond shows the pooled RR from the fixed-effects model and 95% CI. Sexspecific results were presented for the Cancer Prevention Study II Nutrition Cohort (CPS-II). HPFS ⫽ Health Professionals
Follow-up Study; NHS ⫽ Nurses Health Study.
966
Annals of Neurology
Vol 58
No 6
December 2005
fore unable to estimate the actual dose of ibuprofen
(most pills contain 200mg, but pills at a greater dose
are available), to estimate specific associations for other
nonaspirin NSAIDs (which include several compounds
with different structures and properties), and to create
categories of use based on the biological effects of each
drug.
In summary, the results of this large investigation
based on a prospective assessment of NSAID use favor
the hypothesis that ibuprofen reduces the risk for development of PD. However, there is insufficient information on the optimal dosage, and it remains uncertain whether this effect is mediated by COX
inhibitions or through other mechanisms specific to
ibuprofen and possibly some other selected NSAIDs.
This study was supported by a fast track research grant from the
Michael J. Fox Foundation for Parkinson Research (A.A.), a gift
from the Kinetics Foundation (A.A.), and the NIH (National Institute of Neurological Disorders and Stroke, NS48468, H.C.).
12. Teismann P, Tieu K, Choi DK, et al. Cyclooxygenase-2 is instrumental in Parkinson’s disease neurodegeneration. Proc Natl
Acad Sci U S A 2003;100:5473–5478.
13. Yan Q, Zhang J, Liu H, et al. Anti-inflammatory drug therapy
alters beta-amyloid processing and deposition in an animal
model of Alzheimer’s disease. J Neurosci 2003;23:7504 –7509.
14. Grilli M, Pizzi M, Memo M, Spano P. Neuroprotection by
aspirin and sodium salicylate through blockade of NF-kappaB
activation. Science 1996;274:1383–1385.
15. Kataoka M, Tonooka K, Ando T, et al. Hydroxyl radical scavenging activity of nonsteroidal anti-inflammatory drugs. Free
Radic Res 1997;27:419 – 427.
16. Asanuma M, Nishibayashi-Asanuma S, Miyazaki I, et al. Neuroprotective effects of non-steroidal anti-inflammatory drugs by
direct scavenging of nitric oxide radicals. J Neurochem 2001;
76:1895–1904.
17. Casper D, Yaparpalvi U, Rempel N, Werner P. Ibuprofen protects dopaminergic neurons against glutamate toxicity in vitro.
Neurosci Lett 2000;289:201–204.
18. Milatovic D, Zaja-Milatovic S, Montine KS, et al. Pharmacologic suppression of neuronal oxidative damage and dendritic degeneration following direct activation of glial innate
immunity in mouse cerebrum. J Neurochem 2003;87:
1518 –1526.
We thank the study participants for their continuous contributions
to the American Cancer Society’s Cancer Prevention Study II Nutrition Cohort and Dr Y. Song for his technical help.
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Chen et al: NSAID Use and PD Risk
967
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