ORIGINAL INVESTIGATION

Analgesic Use and Risk of Subsequent Hypertension

in Apparently Healthy Men
Tobias Kurth, MD, ScD; Charles H. Hennekens, MD, DrPH; Til Strmer, MD, MPH; Howard D. Sesso, ScD, MPH;
Robert J. Glynn, PhD, ScD; Julie E. Buring, ScD; J. Michael Gaziano, MD, MPH

Background: Prospective studies have suggested that

women who self-select for use of analgesics have an increased risk of hypertension, but data in men are sparse.
We tested whether apparently healthy male physicians
who reported analgesic use had an increased risk of subsequent hypertension.
Methods: Prospective cohort study of 8229 participants in the Physicians Health Study who were free of
hypertension and completed detailed analgesic questionnaires. Hypertension was defined as self-reported blood
pressure of 140/90 mm Hg or higher or use of antihypertensive medication.
Results: After a mean of 5.8 years follow-up, 2234

men (27.2%) reported subsequent hypertension. We

categorized the cumulative analgesic use in quintiles.
After adjusting for potential confounders, men in the
highest quintile had no statistically significant
increased risk of hypertension (hazard ratio, 1.12; 95%

Author Affiliations are listed at

the end of this article.

confidence interval, 0.97-1.31) when compared with

those in the lowest quintile. In subgroup analyses, we
evaluated the cumulative use of nonsteroidal antiinflammatory drugs, acetaminophen, and aspirin.
Compared with never users, men who reported consuming at least 2500 pills had hazard ratios of 1.05
(95% confidence interval, 0.89-1.24) for nonsteroidal
anti-inflammatory drugs, 1.08 (95% confidence interval, 0.87-1.34) for acetaminophen, and 1.16 (95%
confidence interval, 0.92-1.48) for aspirin. The results
were similar for analgesic use in the year preceding the
analgesic questionnaire.
Conclusion: In this large cohort, apparently healthy male
physicians who self-selected for analgesic use had no significantly increased risk of subsequent hypertension, although a small to moderately increased risk cannot be
excluded in observational studies.

Arch Intern Med. 2005;165:1903-1909

YPERTENSION IS A MAJOR

independent risk factor

for cardiovascular disease, including stroke and
myocardial infarction, as
well as for heart failure and renal disease.1 In the United States, obesity is perhaps the major contributor to increasing
rates of hypertension.2 Nonetheless, other
potentially modifiable determinants merit
consideration. The role of prostaglandins (PGs) in blood pressure regulation has
been well studied.3 The imbalances between vasodilator and vasoconstrictor PGs
may affect blood pressure.4 On the partial basis of their ability to inhibit PG production, nonsteroidal anti-inflammatory
drugs (NSAIDs) have been postulated to
increase blood pressure.5
Two meta-analyses6,7 of randomized
trials of small sample size and short duration indicate that NSAIDs but not aspirin
increase blood pressure. In both analyses,
the overall effect sizes were small and
reached statistical significance only among
the subgroups of patients with hypertension or who took antihypertensive drugs.
One case-control study8 showed that indi-

(REPRINTED) ARCH INTERN MED/ VOL 165, SEP 12, 2005

1903

viduals prescribed NSAIDs were more likely

to initiate antihypertensive drug therapy
when compared with those not prescribed these drugs. Two large prospective cohort studies9,10 in women evaluated
whether self-selection for analgesic use was
associated with an increased risk of hypertension. One study9 showed increased risks
of hypertension among users of NSAIDs and
acetaminophen but not aspirin, and the
other10 showed increased risks for users of
NSAIDs, acetaminophen, and aspirin.
To our knowledge, no large-scale prospective cohort studies have tested this hypothesis in men. We analyzed prospective
data among more than 8000 apparently
healthy male physicians with no history of
hypertension.
METHODS

STUDY POPULATION
The study population was a subgroup from the
Physicians Health Study (PHS), a randomized trial designed to test the benefits and risks
of aspirin (325 mg every other day) or beta carotene (50 mg every other day) in the primary

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prevention of cardiovascular disease and cancer among 22 071

apparently healthy men aged 40 to 84 years at baseline in 1982.
Participants had no indication or contraindication to the use
of aspirin or other NSAIDs at entry. The design, methods, and
results of the PHS have been described previously.11,12 Posttrial follow-up has continued,13 and this analysis includes data
through March 31, 2004.
Baseline information was collected by mailed questionnaires that included anthropometric, demographic, clinical, and
lifestyle variables. Twice in the first year and yearly thereafter,
follow-up questionnaires were sent out asking about compliance with trial medications; development of adverse effects; newonset clinical cardiovascular disease, cancer, or other diseases; and changes in risk factors.

ASSESSMENT OF ANALGESIC USE

In 1996, participants completed detailed questionnaires about
analgesic use from baseline to the 14-year follow-up. Details
regarding the questionnaire and the results of a validation study14
have been published previously. Participants were asked if they
had taken analgesics 12 or more times since enrolling in the
PHS. Those answering yes were asked how many days per month
and how many pills per day these medications were taken on
average in the preceding year. The participants were also asked
if this pattern had been constant since enrollment. Those answering no were asked to record the number of years for which
this had been the pattern of use and to describe their earlier
use pattern. Aspirin use was determined from the compliance
data reported on each participants annual questionnaire.
The number of pills per year was recorded, and the cumulative number of pills during the 14-year period was calculated. We categorized cumulative analgesic use in quintiles. For
use of NSAIDs, acetaminophen, and aspirin, we used the following 4 categories to be consistent with previous studies14,15:
never use (12 pills), 12 to 1499 pills, 1500 to 2499 pills, and
2500 pills or more pills during the 14-year period.
To evaluate more current use and risk of subsequent hypertension, we categorized the total number of pills used in the
last 12 months preceding the analgesic questionnaire in quintiles. We further categorized the number of pills of specific analgesics as 0, 1 to 14, 15 to 60, and 61 pills or more.

ASSESSMENT OF HYPERTENSION
On the baseline, 24-month, 84-month, 180-month, and 216month questionnaires, participants reported their systolic
and diastolic blood pressures. On the baseline questionnaire,
the 84-month questionnaire, and yearly thereafter, participants were asked whether they had initiated antihypertensive medications. We defined hypertension during follow-up
according to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment
of High Blood Pressure guidelines16: a systolic blood pressure of 140 mm Hg or higher, a diastolic blood pressure of
90 mm Hg or higher, or any use of antihypertensive medications.

STATISTICAL ANALYSIS
In 1996, 19 390 participants returned the analgesic questionnaire. Of those, we excluded 11 161 participants, of whom 11 134
had missing information on hypertension or developed cardiovascular events and 27 reported renal disease before completion of the questionnaire, leaving 8229 participants without hypertension at the beginning of follow-up. To estimate the
relationships of cumulative analgesic use and use in the year
(REPRINTED) ARCH INTERN MED/ VOL 165, SEP 12, 2005
1904

preceding the 1996 analgesic assessment with risk of subsequent hypertension, we used the Cox proportional hazards
model.17 We tested the proportional hazards assumption and
found no violation. We censored participants if they reported
cardiovascular events before reporting hypertension because
such an event might have differentially affected blood pressure and analgesic use. We calculated age- and multivariableadjusted hazard ratios (HRs) and their 95% confidence intervals (CIs). We included missing information for each of the
analgesic classes as a separate category in the models. We used
the most recent information for any of the covariates before the
time point of the analgesic questionnaire and 3 multivariable
models. Model 1 controlled for age (as an exponential term),
body mass index (in quintiles), and other analgesic categories
(except for the model including cumulative analgesic use). Model
2 controlled for all variables in model 1 plus indicators of chronic
pain, including any report of arthritis, headache, or migraine,
as well as headache and migraine frequency (6 vs 6 times).
Model 3 controlled for all variables in model 2 plus potential
risk factors for hypertension, including alcohol consumption
(1 drink/wk; 2-6 drinks/wk; 1 drink/d), exercise (1/wk;
1-4/wk; 5/wk), smoking (never, past, current), history of diabetes mellitus, history of high cholesterol or lipid-lowering treatment, parental history of premature myocardial infarction, and
systolic and diastolic blood pressures. We calculated P values
for trend across cumulative analgesic use categories, excluding the missing information category.
We evaluated whether there was effect modification by age
by performing stratified analyses among participants 59 years
or younger, 60 to 69 years, or 70 years or older. The use of body
mass index as a continuous variable and different classifications for alcohol consumption, exercise, and headache frequency yielded similar results.
RESULTS

The age range of the 8229 apparently healthy men was

53 to 97 years (meanSD age, 63.97.7 years). After a
mean of 5.8 years follow-up (47 794 person-years), 2234
men (27.2%) reported subsequent hypertension. In
Table 1, we summarize age-adjusted characteristics of
participants according to cumulative analgesic use categories. Men who consumed 2500 pills or more of any
of the analgesics were heavier and reported more headaches or migraine headaches compared with participants who reported use of fewer than 12 pills. Participants in the highest intake category of NSAIDs or
acetaminophen were more likely to report arthritis,
whereas participants in the highest intake category of
NSAIDs and aspirin were more likely to report a parental history of premature myocardial infarction.
Table 2 gives the age- and multivariable-adjusted HRs
and their 95% CIs for new-onset hypertension according to cumulative analgesic use categories. After adjustment for age, cumulative analgesic use was statistically
significantly associated with risk of subsequent hypertension. Men in the highest quintile of cumulative analgesic use had an age-adjusted HR of 1.27 (95% CI, 1.101.47) when compared with those in the lowest quintile
(P for trend=.008). The HRs of the specific analgesics
ranged from 1.18 (95% CI, 1.00-1.39) for NSAIDs to 1.23
(95% CI, 0.98-1.56) for aspirin.
The age-adjusted association between cumulative analgesic use and subsequent hypertension was reduced to
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Table 1. Characteristics of Participants According to Cumulative Analgesic Use Categories*

Cumulative Analgesic Use, No. of Pills
12

Characteristic
No. of physicians
Age, mean SE, y
Body mass index, mean SE
Body mass index 30
Physical activity sessions per week
1
1-4
5
Alcoholic drinks
1/wk
2-6/wk
1/d
Smoking
Never
Past
Current
Diabetes mellitus
High cholesterol
Parental history of premature myocardial infarction
Arthritis
Headache
Migraine
No. of physicians
Age, mean SE, y
Body mass index, mean SE
Body mass index 30
Physical activity sessions per week
1
1-4
5
Alcoholic drinks
1/wk
2-6/wk
1/d
Smoking
Never
Past
Current
Diabetes mellitus
High cholesterol
Parental history of premature myocardial infarction
Arthritis
Headache
Migraine
No. of physicians
Age, mean SE, y
Body mass index, mean SE
Body mass index 30
Physical activity sessions per week
1
1-4
5
Alcoholic drinks
1/wk
2-6/wk
1/d
Smoking
Never
Past
Current
Diabetes mellitus
High cholesterol
Parental history of premature myocardial infarction
Arthritis
Headache
Migraine

12-1499

1500-2499

Nonsteroidal Anti-inflammatory Drug Use

4188
2631
347
64.0 0.02
63.9 0.03
63.9 0.08
25.0 0.05
25.3 0.06
25.3 0.16
5.4
6.6
7.8

2500

Missing Information

575
63.9 0.06
25.8 0.12
9.5

488
64.0 0.07
25.3 0.13
6.2

18.8
62.3
18.9

17.3
66.5
16.2

15.6
69.5
14.9

13.3
68.0
18.7

16.4
65.0
18.6

37.7
48.7
13.6

32.5
51.7
15.8

30.5
53.7
15.8

25.9
55.6
18.5

36.4
49.7
13.9

54.4
41.6
4.0
0.9
21.4
7.9
14.8
46.2
11.3

52.8
43.7
3.5
1.2
21.1
10.0
23.3
57.7
13.5

53.1
44.1
2.7
0.7
25.4
9.2
30.7
58.0
12.5

48.3
48.2
3.6
0.9
24.1
10.5
43.5
60.8
14.6

50.6
43.6
5.9
1.2
20.9
10.1
25.5
56.1
12.8

264
64.0 0.09
25.1 0.18
6.0

310
64.0 0.08
25.5 0.17
7.9

848
63.9 0.05
25.2 0.10
5.8

Acetaminophen Use
4290
2517
64.0 0.02
63.9 0.03
25.1 0.05
25.2 0.06
5.9
6.7
17.6
63.5
18.9

17.7
65.6
16.7

20.1
64.5
15.4

15.6
68.7
15.7

16.9
64.8
18.3

34.5
50.0
15.5

34.4
51.7
13.9

40.8
47.7
11.5

38.0
48.9
13.1

35.4
50.3
14.3

53.8
42.0
4.2
1.0
21.0
8.9
18.1
44.0
10.6

52.5
44.2
3.3
0.8
21.5
8.6
21.4
60.9
13.7

59.4
37.6
2.9
0.5
25.4
7.8
25.7
66.4
18.1

46.0
49.4
4.6
0.8
24.4
10.2
30.4
67.5
19.5

51.6
44.7
3.7
1.7
24.6
11.3
26.4
58.7
13.2

2723
63.9 0.03
25.0 0.06
5.1

1552
63.9 0.04
25.4 0.08
8.2

821
64.0 0.05
25.3 0.10
6.5

333
63.9 0.08
25.0 0.16
16.7

Aspirin Use
2800
63.9 0.03
25.1 0.06
6.2

22.4
59.4
18.2

19.0
63.7
17.3

17.8
63.9
18.3

14.6
66.3
19.2

16.2
66.1
17.8

43.8
46.8
9.5

36.8
49.0
14.2

34.9
49.5
15.6

30.9
54.8
14.3

31.7
53.0
15.3

50.6
46.2
3.2
1.1
18.2
5.8
22.4
42.8
12.0

54.5
41.6
4.0
0.9
20.4
7.5
20.5
49.2
12.2

54.6
41.3
4.1
0.9
21.9
9.7
17.8
50.7
10.9

50.0
46.3
3.6
1.1
22.8
10.5
22.5
58.8
14.4

49.8
46.6
3.7
1.4
25.3
10.4
25.8
60.7
14.5

*Data are given as percentages unless otherwise indicated and are adjusted for age in 5-year increments.
Calculated as weight in kilograms divided by the square of height in meters.

(REPRINTED) ARCH INTERN MED/ VOL 165, SEP 12, 2005

1905

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Table 2. Hazard Ratios for Subsequent Hypertension According to Cumulative Analgesic Use*
Cumulative Analgesic Use,
No. of Pills

No. of Physicians
(No. With Hypertension)

Model 2

Model 3

Cumulative Analgesic Use in Quintiles

1.00
1.00
1.14 (0.98-1.32)
1.13 (0.97-1.31)
1.00 (0.85-1.16)
1.00 (0.86-1.17)
1.09 (0.94-1.27)
1.10 (0.94-1.28)
1.27 (1.10-1.47)
1.21 (1.05-1.41)
1.09 (0.95-1.26)
1.07 (0.92-1.23)

1.00
1.13 (0.97-1.31)
1.00 (0.86-1.16)
1.08 (0.93-1.26)
1.19 (1.03-1.38)
1.05 (0.91-1.21)

1.00
1.10 (0.95-1.28)
0.99 (0.85-1.15)
1.03 (0.88-1.20)
1.12 (0.97-1.31)
1.05 (0.90-1.21)

Nonsteroidal Anti-inflammatory Drug Use

1.00
1.00
1.05 (0.96-1.16)
1.05 (0.95-1.16)
0.94 (0.75-1.17)
0.88 (0.71-1.11)
1.18 (1.00-1.39)
1.10 (0.94-1.30)
1.08 (0.91-1.29)
1.05 (0.87-1.26)

1.00
1.04 (0.95-1.15)
0.88 (0.70-1.10)
1.09 (0.93-1.29)
1.04 (0.87-1.24)

1.00
1.04 (0.94-1.15)
0.87 (0.69-1.10)
1.05 (0.89-1.24)
1.02 (0.85-1.23)

Age-Adjusted

Model 1

0-1401
1402-2139
2140-2793
2794-4511
4512
Missing information

1309 (326)
1313 (370)
1311 (335)
1312 (352)
1311 (394)
1673 (457)

12
12-1499
1500-2499
2500
Missing information

4188 (1128)
2631 (712)
347 (83)
575 (170)
488 (141)

12
12-1499
1500-2499
2500
Missing information

4290 (1204)
2517 (607)
264 (87)
310 (97)
848 (239)

Acetaminophen Use
1.00
0.87 (0.79-0.96)
1.22 (0.98-1.52)
1.20 (0.98-1.58)
1.01 (0.88-1.16)

1.00
0.87 (0.79-0.96)
1.19 (0.96-1.49)
1.16 (0.94-1.43)
1.04 (0.86-1.25)

1.00
0.86 (0.78-0.95)
1.17 (0.94-1.64)
1.13 (0.91-1.40)
1.03 (0.86-1.25)

1.00
0.86 (0.77-0.95)
1.17 (0.93-1.46)
1.08 (0.87-1.34)
1.02 (0.85-1.23)

12
12-1499
1500-2499
2500
Missing information

333 (83)
2800 (737)
2723 (726)
1552 (463)
821 (225)

Aspirin Use
1.00
1.06 (0.84-1.33)
1.07 (0.85-1.34)
1.23 (0.98-1.56)
1.08 (0.84-1.39)

1.00
1.05 (0.84-1.33)
1.07 (0.85-1.34)
1.20 (0.95-1.53)
1.01 (0.76-1.34)

1.00
1.05 (0.83-1.32)
1.06 (0.84-1.34)
1.19 (0.94-1.51)
1.00 (0.75-1.33)

1.00
1.05 (0.83-1.32)
1.06 (0.84-1.34)
1.16 (0.92-1.48)
1.02 (0.76-1.36)

*Data are given as age-adjusted and multivariable-adjusted hazard ratio (95% confidence interval) unless otherwise indicated.
Adjusted for age as exponential term. Using the test for trend across categories, excluding the missing information category, the age-adjusted, model 1, model
2, and model 3 values, respectively, are as follows: cumulative analgesic use: P = .008, P = .03, P = .08, and P = .30; nonsteroidal anti-inflammatory drug use:
P = .088, P = .40, P = .52, and P = .80; acetaminophen use: P = .47, P = .60, P = .88, and P = .85; and aspirin use: P = .01, P = .03, P = .04, and P = .07.
Model 1 adjusted for age, body mass index, and other analgesic classes (with the exception of the model including total analgesic use).
Model 2 adjusted for all variables in model 1 plus history of arthritis, history of headache or migraine, and headache and migraine frequency.
Model 3 adjusted for all variables in model 2 plus smoking, exercise, alcohol consumption, diabetes, high cholesterol, parental history of premature
myocardial infarction, and systolic and diastolic blood pressure.

nonsignificance after adjusting for body mass index, indicators of acute and chronic pain, and risk factors for hypertension. Compared with men in the lowest quintile of
cumulative analgesic use, those in the highest quintile had
a multivariable-adjusted (model 3) HR of 1.12 (95% CI,
0.97-1.31) (Table 2). Compared with never users, those
who consumed 2500 pills or more during the 14-year period of recorded exposures had HRs of 1.05 (95% CI, 0.891.24) for NSAIDs, 1.08 (95% CI, 0.87-1.34) for acetaminophen, and 1.16 (95% CI, 0.92-1.48) for aspirin.
We also evaluated the association between selfselection for cumulative and specific analgesic use in the
year before the questionnaire and risk of subsequent hypertension (Table 3). We found neither significant nor
consistent relationships of cumulative analgesic use in
quintiles and various categories of NSAID, acetaminophen, or aspirin use with subsequent hypertension. After adjusting for all potential confounding factors, men
in the highest quintile (consumption of 517 pills) had
an HR for hypertension of 1.05 (95% CI, 0.91-1.21) when
compared with those in the lowest quintile. We found
no statistically significant association between any specific analgesic use in the year before the analgesic questionnaire and risk of subsequent hypertension, except
perhaps for acetaminophen. There was no apparent modi(REPRINTED) ARCH INTERN MED/ VOL 165, SEP 12, 2005
1906

fication by age of the lack of effects of self-selection for cumulative analgesic use and use of NSAIDs, acetaminophen,
or aspirin for cumulative use or use in the last year and
subsequent hypertension.
COMMENT

In this cohort of 8229 apparently healthy men free of hypertension at the start of follow-up, those who selfselected for cumulative analgesic use of NSAIDs, acetaminophen, or aspirin had no significantly increased risk
of subsequent hypertension after adjustments for all potential confounding variables. Our data also showed a lack
of association between apparently healthy men who selfselected for recent analgesic use in the preceding year of
the assessment and risk of subsequent hypertension. For
specific analgesic use, the finding appeared to be null for
NSAIDs and aspirin but raised the possibility of a small
to moderate increase for acetaminophen. None of the null
findings appeared to be modified by age.
Our findings are consistent with those from randomized trials and their meta-analyses on the use of NSAIDs
in a subgroup of normotensive subjects6,7 and on aspirin
use in normotensive and hypertensive subjects,6,7,18,19 as well
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Table 3. Hazard Ratios for Subsequent Hypertension According to Analgesic Use in the Year Preceding the 1996 Assessment*
Analgesic Use in the
Year Preceding the 1996
Assessment, No. of Pills

No. of Physicians
(No. With
Hypertension)

Model 2

Model 3

Cumulative Analgesic Use in Quintiles

1.00
1.00
1.01 (0.88-1.16)
1.00 (0.87-1.15)
1.03 (0.90-1.19)
1.03 (0.90-1.18)
1.08 (0.95-1.24)
1.07 (0.94-1.23)
1.20 (1.04-1.38)
1.14 (0.99-1.32)
1.06 (0.93-1.22)
1.04 (0.90-1.19)

Age-Adjusted

Model 1

1.00
0.99 (0.87-1.14)
1.01 (0.88-1.17)
1.06 (0.92-1.21)
1.12 (0.97-1.29)
1.02 (0.89-1.17)

1.00
1.01 (0.88-1.16)
0.99 (0.86-1.14)
1.02 (0.89-1.17)
1.05 (0.91-1.21)
1.04 (0.90-1.19)

0-156
157-204
205-299
300-516
517
Missing information

1962 (521)
1319 (341)
1278 (336)
1333 (370)
1059 (316)
1278 (350)

0
1-14
15-60
61
Missing information

4375 (1177)
286 (68)
1402 (376)
1924 (541)
242 (72)

Nonsteroidal Anti-inflammatory Drug Use

1.00
1.00
0.87 (0.68-1.11)
0.87 (0.68-1.11)
1.06 (0.95-1.20)
1.06 (0.94-1.19)
1.11 (0.99-1.21)
1.04 (0.94-1.19)
1.11 (0.87-1.40)
1.08 (0.84-1.38)

1.00
0.86 (0.67-1.10)
1.05 (0.93-1.18)
1.03 (0.93-1.15)
1.07 (0.83-1.37)

1.00
0.89 (0.70-1.14)
1.03 (0.91-1.16)
1.01 (0.91-1.13)
1.09 (0.85-1.41)

0
1-14
15-60
61
Missing information

7176 (1930)
130 (32)
207 (62)
129 (47)
587 (163)

Acetaminophen Use
1.00
1.00
0.96 (0.68-1.36)
0.95 (0.66-1.35)
1.14 (0.88-1.46)
1.07 (0.83-1.38)
1.48 (1.11-1.97)
1.43 (1.07-1.91)
1.03 (0.88-1.21)
0.98 (0.77-1.25)

1.00
0.93 (0.65-1.33)
1.06 (0.82-1.36)
1.39 (1.04-1.86)
0.98 (0.77-1.25)

1.00
0.95 (0.67-1.36)
1.08 (0.84-1.40)
1.34 (1.00-1.80)
1.00 (0.78-1.28)

0
1-14
15-60
61
Missing information

316 (80)
15 (1)
129 (33)
7112 (1934)
657 (186)

Aspirin Use
1.00
0.24 (0.03-1.75)
1.00 (0.67-1.50)
1.09 (0.87-1.36)
1.13 (0.87-1.46)

1.00
0.31 (0.04-2.19)
1.01 (0.67-1.52)
1.10 (0.87-1.38)
1.11 (0.81-1.53)

1.00
0.30 (0.04-2.11)
1.10 (0.73-1.67)
1.08 (0.85-1.35)
1.10 (0.80-1.51)

1.00
0.31 (0.04-2.21)
1.02 (0.68-1.53)
1.10 (0.88-1.38)
1.12 (0.82-1.54)

*Data are given as age-adjusted and multivariable-adjusted hazard ratio (95% confidence interval) unless otherwise indicated. For an explanation of the 3
models, see the footnotes to Table 2.
Adjusted for age as exponential term. Using the test for trend across categories, excluding the missing information category, the age-adjusted, model 1, model
2, and model 3 values, respectively, are as follows: cumulative analgesic use: P = .01, P = .04, P = .11, and P = .54; nonsteroidal anti-inflammatory drug use: P = .06,
P = .33, P = .46, and P = .75; acetaminophen use: P = .01, P = .03, P = .06, and P = .06; and aspirin use: P = .30, P = .29, P = .30, and P = .47.

as from 2 small randomized trials among hypertensive subjects on the use of acetaminophen.20,21 With regard to aspirin, our findings are also consistent with 2 large observational cohort studies.9,22
In contrast to our data, 2 previous large prospective
cohort studies suggested that normotensive women who
self-selected for NSAIDs,9,10 acetaminophen,9,10 and aspirin10 use had higher risks of subsequent hypertension
using similar definitions. The first study9 showed that
women who used NSAIDs or acetaminophen had about
a 2-fold increased risk of developing hypertension after
a mean of 2 years follow-up. The increased risk was apparent and statistically significant for women who consumed NSAIDs 5 to 14 days per month or acetaminophen 1 to 4 days per month, and it increased with higher
dosage. The effect estimates of the age-adjusted models,
however, were substantially attenuated after controlling for additional risk, suggesting that residual confounding remains a plausible alternative explanation.
The second study10 suggested that women who selfselected for even infrequent use of NSAIDs, acetaminophen, or aspirin had an increased risk of hypertension. After adjusting for potential confounders, those in the highest
intake categories (22 d/mo) had statistically significant
HRs of 1.35 for NSAIDs, 1.20 for acetaminophen, and 1.21
for aspirin. This study suggested that a significantly in(REPRINTED) ARCH INTERN MED/ VOL 165, SEP 12, 2005
1907

creased risk of hypertension was apparent among women

who self-selected for NSAIDs, acetaminophen, or aspirin
5 to 14 days per month. Although chance effect is unlikely in this large cohort, uncontrolled and uncontrollable confounding remains plausible because the observed effects are small to moderate.
A large case-control study8 compared recent NSAID
users among patients with newly initiated antihypertensive drug therapy and NSAID nonusers. After adjusting
for potential confounding factors, the odds ratio for recent NSAID users compared with nonusers was 1.66 for
newly initiated antihypertensive drugs. The effect estimate increased with increasing daily NSAID dose. The
available data, however, did not allow adjustments for
confounding by risk factors for hypertension.
Two meta-analyses6,7 of randomized trials on NSAIDs
and blood pressure have been published. The first metaanalysis6 did not report overall effects but provided subgroup analyses. The subgroup of normotensive participants had little if any increase in mean arterial pressure
(mean, 1.1 mm Hg), whereas hypertensive participants
had an increase of 3.3 mm Hg. In the second metaanalysis,7 individuals assigned to NSAIDs had a statistically significant increase in supine mean arterial blood
pressure of 5.0 mm Hg. This significant increase in blood
pressure was apparent among the subgroup of patients
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2005 American Medical Association. All rights reserved.

with controlled hypertension. As in the other metaanalysis, the subgroup of normotensive subjects had no
statistically significant increase in mean blood pressure.
Both meta-analyses showed no association between aspirin use and hypertension. In addition, the individual
trials were of small sample size, and the duration of analgesic use was short (7 weeks).
Two cross-sectional studies23,24 showed no overall associations between NSAID use and hypertension, but the
subgroup of patients using NSAIDs and antihypertensive drugs had significantly higher blood pressures. The
lack of a temporal relationship between exposure and outcome limits the interpretability of the results.
Analgesics may affect blood pressure through several
mechanisms, most of which are mediated through kidney or systemic cyclooxygenase-2specific inhibition of
PGs.4,25-28 The distortion of the balance between the vasodilators PGI2 and PGE2 and the vasoconstrictors PGF2
and thromboxane A2 may be particularly relevant. In the
kidneys, the inhibition of PGs may lead to sodium and
water retention.27-29 In addition, PGs inhibit vascular endothelial production of endothelin-1, which may lead to
increased blood pressure through increased peripheral
resistance.30 Nonsteroidal anti-inflammatory drugs,31 aspirin,32 and, to a lesser degree, acetaminophen33,34 have
been associated with inhibition of PGs. It remains unclear whether the postulated biological effects of analgesics on PGs lead to a temporary increase in blood pressure or to sustained effects among normotensive subjects.
Among patients treated for hypertension, NSAIDs may
interact with antihypertensive drug therapies, leading to
an increase in blood pressure.6,7,23,24,35
Our study has several strengths, including its large
sample size and number of reports of new-onset hypertension, high follow-up rates, detailed assessment of over-thecounter analgesics, and use of physicians as the study population, which reduces the potential for confounding due
to variability in access to medical care, educational attainment, and socioeconomic status. In addition, we controlled for many potential confounding factors, including
markers of chronic pain. Furthermore, participants in the
PHS had no indication or contraindication for aspirin or
NSAID use at enrollment into the PHS, which may reduce
any residual confounding by indication.
Several limitations should be considered. Although we
controlled for many risk factors for hypertension, residual
and unmeasured confounding is possible because the study
design is observational. We are not aware of any biologically plausible confounding factors that would yield substantially increased effect estimates of the association between analgesic use and hypertension. Despite the lack of
association between analgesic use in the year preceding our
assessment and risk of hypertension, cumulative analgesic use may not be a risk factor for the development of
hypertension but rather short-term use or a different use
pattern, as some studies6,7,9 suggested. Participants selfreported their analgesic use; thus, misclassification of exposure is possible. Furthermore, we had no information
regarding specific dosage of these analgesics and no detailed information about the pattern of use. In a substudy,14 the correlation between a self-reported retrospective questionnaire and a structured telephone interview of
(REPRINTED) ARCH INTERN MED/ VOL 165, SEP 12, 2005
1908

analgesic use was moderate to good (correlation coefficient, 0.40-0.76), and most participants used standard overthe-counter doses. With regard to potential misclassification, it is unlikely that physicians who regularly used
analgesics would report occasional use and vice versa. In
addition, none of the subcategories of analgesics were associated with subsequent hypertension. It has been suggested that individual NSAIDs have different effects on blood
pressure. Because we had information only on overall
NSAID use, we cannot exclude the possibility that some
NSAIDs are associated with an increased risk of hypertension. However, other observational studies8-10 found
increased risk with overall NSAID use. We also had no information on cyclooxygenase-2 inhibitors. A recent metaanalysis36 of randomized trials found that use of cyclooxygenase-2 inhibitors was associated with a significant increase
in blood pressure of 3.85 mm Hg compared with placebo
and 2.83 mm Hg compared with NSAIDs. This metaanalysis further demonstrated an increased risk of developing hypertension when use of cyclooxygenase-2 inhibitors was compared with placebo (relative risk, 1.61; 95%
CI, 0.91-2.84) or with nonselective NSAIDs (relative risk,
1.25; 95% CI, 0.87-1.78), although this was not statistically significant.
The information on hypertension in our study was selfreported, which may have led to misclassification. However, physicians are known to report medical conditions and treatment accurately, and we have no reason
to believe that reports of hypertension were influenced
by analgesic use. Although we found no effect modification by age, we cannot exclude the possibility that the
lack of association is not generalizable to younger men
because our study did not include men younger than 53
years. Furthermore, participants of the PHS were predominantly white. Nonetheless, differential biological effects of analgesic use on blood pressure in different populations seem unlikely. We believe the discrepancies
between findings in men and women are more apparent
than real and are likely to be explained by residual confounding.
Despite these and perhaps other limitations, we believe the most plausible interpretation of our data is that
apparently healthy male physicians who self-select for analgesic use did not have a significantly increased risk of
subsequent hypertension. These data suggest that in apparently healthy men, the use of analgesics is unlikely
to produce large increases in hypertension, although a
small to moderately increased risk cannot be excluded
in any observational study.
Accepted for Publication: May 2, 2005.
Author Affiliations: Divisions of Aging (Drs Kurth, Sesso,
Buring, and Gaziano), Preventive Medicine (Drs Kurth,
Strmer, Sesso, Glynn, Buring, and Gaziano), and Pharmacoepidemiology and Pharmacoeconomics (Drs Strmer
and Glynn), Department of Medicine, Brigham and Womens Hospital, Harvard Medical School Boston, Mass; Departments of Epidemiology (Drs Kurth, Sesso, and Buring) and Biostatistics (Dr Glynn), Harvard School of Public
Health, Boston; Department of Ambulatory Care and Prevention, Harvard Medical School (Dr Buring) Boston; Massachusetts Veterans Epidemiologic Research CenWWW.ARCHINTERNMED.COM

2005 American Medical Association. All rights reserved.

ter, Boston VA Healthcare System (Dr Gaziano), Boston; Departments of Medicine and Epidemiology and Public Health, University of Miami School of Medicine, Miami,
Fla; and Department of Biomedical Science, Center of
Excellence, Florida Atlantic University, Boca Raton (Dr
Hennekens).
Correspondence: Tobias Kurth, MD, ScD, Division of Preventive Medicine, Department of Medicine, Brigham and
Womens Hospital, Harvard Medical School, 900 Commonwealth Ave E, Boston, MA 02215 (tkurth@rics.bwh
.harvard.edu).
Financial Disclosure: Dr Kurth is the principal investigator of 2 investigator-initiated unrestricted research
grants, one from McNeil and one from Bayer. Dr
Hennekens is the principal investigator or co-principal
investigator on 2 investigator-initiated research grants by
Bayer. Dr Hennekens serves as a consultant for Agatston Research Institute, Amgen, AstraZeneca, Bayer AG,
Bristol-Myers Squibb, Chattem, Delaco, the Food and
Drug Administration, GlaxoSmithKline, McNeil Consumer & Specialty Pharmaceuticals, the National Institutes of Health, Novartis, Pfizer, Reliant, TAP, and
UpToDate. Dr Gaziano is the principal investigator or
co-principal investigator of investigator-initiated research grants from BASF, Roche Pharmaceuticals,
Wyeth Pharmaceuticals, and McNeil Consumer Products; serves as a consultant for McNeil Consumer &
Specialty Pharmaceuticals, Wyeth Pharmaceuticals,
Merck, and Nutraquest; and is on the Speakers Bureau
for Pfizer.
Funding/Support: This work was supported by investigator-initiated research grants CA 34944, CA 40360, HL
26490, and HL 34595 from the National Institutes of
Health, Bethesda, Md, and by an investigator-initiated research grant from McNeil Consumer & Specialty Pharmaceuticals, Fort Washington, Pa.
Role of the Sponsor: The sponsors had no role in the study
design, data collection, analyses, interpretation, or drafting of the manuscript.
Disclaimer: The authors were responsible for the data
collection and had full access to the data at all times.
Acknowledgment: We are indebted to the participants
in the PHS for their outstanding commitment and cooperation; to the entire PHS staff for their expert and unfailing assistance; and to Vadim Bubes, PhD, for programming assistance.
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