Frequency of Analgesic Use and Risk of Hypertension in Younger Women

Background  In addition to their antipyretic, anti-inflammatory, and pain-relieving effects, analgesics may interfere with blood pressure regulation. However, little prospective information is available on the association between analgesic use and the risk of hypertension.

Methods  We performed a prospective study of 80 020 women aged 31 to 50 years who participated in the Nurses' Health Study II and had no previous history of hypertension. Frequency of use (in days per month) of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and acetaminophen was collected by mailed questionnaire in 1995. Incident cases of physician-diagnosed hypertension were identified by self-report on the 1997 biennial questionnaire.

Results  During 164 090 person-years of follow-up, 1650 incident cases of hypertension were identified. At least 1 d/mo, 51.2% of the cohort used aspirin, 76.7% used NSAIDs, and 72.5% used acetaminophen. After adjusting for age, all 3 classes of analgesics were associated with an increased risk of incident hypertension (P<.001 for trend). After further adjustment for all 3 analgesics and other potential risk factors, only NSAIDs and acetaminophen (P<.001 for trend for both) were significantly associated with risk of hypertension. Compared with nonusers, the relative risk of hypertension for women taking NSAIDs 22 d/mo or more was 1.86 (95% confidence interval, 1.51-2.28) and for those taking acetaminophen 22 d/mo or more was 2.00 (95% confidence interval, 1.52-2.62).

Conclusions  Use of NSAIDs and use of acetaminophen were significantly associated with increased risk of hypertension, but aspirin use was not. A substantial proportion of hypertension in the United States, and the associated morbidity and mortality, may be due to the use of these medications.

ANALGESIC USE is common, particularly in women.¹ In 1999, more than $2 billion was spent on over-the-counter analgesic medications in the United States alone (Roland Schneider, MD, Boehringer-Ingelheim, e-mail, August 24, 2000). The antipyretic, anti-inflammatory, and pain-relieving actions of analgesics are well-known. Analgesics may interfere with blood pressure regulation by altering production of vasodilatory prostaglandins,² decreasing renal sodium excretion,³ or inhibiting nitric oxide synthetase.^4,5

Results of previous studies have suggested that use of nonsteroidal anti-inflammatory drugs (NSAIDs) causes a small increase in blood pressure⁶ and increases the risk of hypertension,⁷ whereas aspirin^6,8 and acetaminophen⁹ use do not. However, most studies have focused on changes in blood pressure in individuals taking antihypertensive medication. Despite the high prevalence of use of analgesics, often for prolonged periods, scant information is available on the long-term risk of incident hypertension.

To address this issue, we prospectively examined the association between frequency of use of the 3 analgesic classes and risk of incident hypertension among 80 020 young women with no previous history of hypertension.

In 1989, 116 671 female registered nurses (age range, 25-42 years) from 15 states completed and returned the initial questionnaire and constitute the Nurses' Health Study II cohort. This cohort is followed by means of biennial mailed questionnaires that inquire about lifestyle practices, other exposures of interest, and the incidence of physician-diagnosed disease. The follow-up rate for the cohort exceeds 90%.

Detailed information on analgesic use was first collected on the 1995 biennial questionnaire. For this study of analgesic use and the risk of hypertension between 1995 and 1997, participants were selected based on having responded to the longer version of the 1995 biennial questionnaire (n = 91 744). After excluding women with a previously reported history of hypertension (n = 8999) and those who did not answer the 1997 follow-up questionnaire (n = 2725), 80 020 women were included in the analysis.

We first asked about the frequency of use of each of the 3 classes of analgesics—aspirin, NSAIDs, and acetaminophen—on the 1995 biennial questionnaire. There were 5 response categories of frequency of use (in days per month) for each of the 3 classes of analgesics: none, 1 to 4, 5 to 14, 15 to 21, and 22 or more. Information on number of tablets per day or dose was not collected.

On the 1995 questionnaire, we obtained updated information on age, weight, smoking, and oral contraceptive use. From the 1995 food-frequency portion of the questionnaire, we assessed the intake of alcohol, sodium, potassium, and magnesium. Information available from the 1989 baseline Nurses' Health Study II questionnaire included height, systolic blood pressure (9 response categories), diastolic blood pressure (7 response categories), and family history of hypertension. On the 1991 questionnaire, we inquired about a variety of physical activities from which we calculated a metabolic equivalent task score. Body mass index (BMI) was calculated as weight in kilograms divided by the square of height in meters. On the 1995 questionnaire, we obtained information on the following health screening behaviors in the previous 2 years: sigmoidoscopy or colonoscopy, mammography, breast examination by a clinician, bimanual pelvic examination, and ovarian ultrasound. We obtained information on the 1997 questionnaire on the following health screening behaviors in the previous 2 years: sigmoidoscopy or colonoscopy, mammography, and bimanual pelvic examination.

The baseline and follow-up biennial questionnaires inquired about physician-diagnosed hypertension and the year of diagnosis. Self-reported diagnosis of hypertension was found to be reliable in a similar cohort of women, the Nurses' Health Study I.¹⁰ A study participant was considered to have a history of hypertension if she reported high blood pressure on any questionnaire up to and including the 1995 questionnaire; these women were excluded from the analysis. We included as cases only individuals who first reported hypertension on the 1997 questionnaire and whose date of diagnosis was after the return of the 1995 questionnaire.

For each participant, person-months of follow-up were counted from the date of the return of the 1995 questionnaire to the date of return of the 1997 questionnaire. We allocated person-months of follow-up according to exposure status in 1995 (as indicated by the category of frequency of analgesic use and other variables) and calculated incidence as the number of events divided by person-years of follow-up.

The relative risk (RR)—the incidence rate among women in a particular category of exposure divided by the corresponding rate in the comparison category—was used as the measure of association.¹¹ Age-adjusted RRs were calculated after stratification according to 5-year age categories.¹¹ The Mantel extension test was used to evaluate linear trends across categories of analgesic use.¹² In addition, RRs were adjusted simultaneously for potentially confounding variables using multiple logistic regression analysis. The variables considered in the primary multivariate models were age (5-year categories), BMI (6 categories), alcohol intake (6 categories), sodium intake (quintiles), family history of hypertension in 1989 (yes or no), oral contraceptive use in 1995 (yes or no), and frequency of use of the individual analgesics (5 categories for each analgesic). Categories for missing values for individual variables were also included. In separate models, we also adjusted for age in 1-year increments and BMI in deciles. We also examined models that were further adjusted for current smoker (yes or no), physical activity in 1991 (metabolic equivalent task scores in quintiles), quintiles of intake of potassium and magnesium, and systolic (8 categories) and diastolic (6 categories) blood pressure in 1989. Multivariate tests for trend for the analgesics were assessed using the midpoint of the frequency category. For all RRs, we calculated 95% confidence intervals (CIs). All P values are 2-tailed. This study was approved by the Partners HealthCare institutional review board, Boston, Mass.

During 164 090 person-years of follow-up, 1650 incident cases of hypertension were identified. Overall, 51.2% of the cohort used aspirin at least 1 d/mo, 76.7% used NSAIDs, and 72.5% used acetaminophen. Among women taking an analgesic 22 d/mo or more, NSAIDs were the most commonly used analgesic class, being taken by 4.9% of the cohort.

Characteristics of the cohort according to frequency of use category of the individual analgesics are given in Table 1. Mean age increased with increasing frequency of use of aspirin and NSAIDs. Mean BMI increased with increasing frequency of use of all 3 analgesics. Intake of alcohol and sodium and mean systolic and diastolic blood pressures did not differ substantially by frequency of analgesic use. Oral contraceptive use was least common among women who consumed any of the analgesics 22 d/mo or more. The proportion of women with a family history of hypertension increased with increasing frequency of analgesic use.

Information on frequency of use was unavailable from 27% of the cohort for aspirin, 8% of the cohort for NSAIDs, and 14% of the cohort for acetaminophen. It is unclear why these questions were unanswered by some participants. Overall, the characteristics listed in Table 1 were similar in participants who did and did not answer the specific analgesic questions.

Compared with nonusers of aspirin, the age-adjusted RR of hypertension was significantly increased in women who consumed aspirin, even for those using aspirin 1 to 4 d/mo (RR, 1.18; 95% CI, 1.02-1.35) (Table 2), and the trend was highly statistically significant (P<.001). After adjusting for the use of NSAIDs and acetaminophen and for other potential risk factors, the RRs were attenuated and the trend was only marginally statistically significant (P = .07) (Table 2).

Compared with nonusers of NSAIDs, the age-adjusted RR of hypertension was significantly increased for women who consumed NSAIDs, even for women who used NSAIDs 1 to 4 d/mo (RR, 1.17; 95% CI, 1.02-1.36) (Table 2). There seemed to be a dose response between frequency of use of NSAIDs and risk of hypertension, and the trend was highly statistically significant (P<.001). After adjusting for use of the other 2 analgesics and other risk factors, the RRs for the individual categories were attenuated but remained statistically significant, as did the trend (P<.001 for trend) (Table 2). Compared with nonusers, the RR of hypertension for women taking NSAIDs 22 d/mo or more was 1.86 (95% CI, 1.51-2.28).

Compared with nonusers of acetaminophen, the age-adjusted RR of hypertension was significantly increased, even for women using acetaminophen 1 to 4 d/mo (RR, 1.22; 95% CI, 1.07-1.39) (Table 2). There seemed to be a dose response between frequency of acetaminophen use and risk of hypertension, and the trend was highly statistically significant (P<.001). After adjusting for other risk factors, the RRs for the individual categories were attenuated but remained statistically significant, as did the trend (P<.001 for trend). Compared with nonusers, the RR of hypertension for women taking acetaminophen 22 d/mo or more was 2.00 (95% CI, 1.52-2.62).

Controlling for age in 1-year increments and BMI in deciles or further adjustment for current smoking, physical activity in 1991, intake of potassium and magnesium in 1995, and systolic and diastolic blood pressure in 1989 did not materially change the results. When the analyses were limited to women who had a screening examination in 1995 and 1997 (n = 65 648), the results were not substantially altered. After limiting the analyses to women who had complete information on frequency of use of all 3 analgesics (n = 53 904), the results for the age-adjusted and multivariate models were essentially unchanged.

We explored whether the associations between the different analgesics and risk of incident hypertension were modified by age, BMI, or family history of hypertension. Only family history seemed to modify the associations. The magnitudes of the RRs for all 3 analgesics were generally higher in participants without a family history than in those with a family history. The tests for interaction were marginally statistically significant (aspirin, P = .06; NSAIDs, P = .10; and acetaminophen, P = .09).

The use of NSAIDs and the use of acetaminophen were each strongly associated with risk of developing hypertension in women, and the risks increased with increasing frequency of use. The use of aspirin did not seem to be associated with risk.

To our knowledge, this is the first prospective study to examine frequency of use of the 3 classes of nonnarcotic analgesics, which are readily available without a prescription, in relation to risk of hypertension. The frequency of use of all 3 classes of analgesics is high. More than 70% of the cohort consumed either NSAIDs or acetaminophen at least 1 d/mo. Thus, if these associations are shown to be causal, their contribution to the number of individuals who develop hypertension is likely to be substantial.

The lack of an association between aspirin use and risk of hypertension is consistent with previous studies. Two meta-analyses^6,8 found no change in blood pressure in short-term studies of aspirin use. A prospective study¹³ of Swiss factory workers found that women who had aspirin detected in their urine at baseline were more likely to develop hypertension during follow-up (P = .11), but there was no information on frequency of use or adjustment for other potential risk factors.

Our finding that the use of NSAIDs was associated with an increased risk of hypertension is supported by previous studies. In the meta-analysis by Johnson et al,⁶ use of NSAIDs was associated with an increase in blood pressure of 5.0 mm Hg (95% CI, 1.2-8.7 mm Hg). This effect was most marked in hypertensive individuals who were taking antihypertensive medication.⁶ A meta-analysis by Pope and colleagues⁸ found that the effect of NSAID use on blood pressure varied considerably. Notably, 92% of individuals in that meta-analysis were hypertensive. In a case-control study, Gurwitz et al⁷ found that among individuals 65 years and older, the odds ratio for the initiation of antihypertensive therapy for recent users of NSAIDs was 1.66 compared with nonusers. The interpretation of previously published studies is limited by several factors. The prospective studies usually lasted no more than a few weeks. Sample sizes tended to be small, and little information was available on younger women. Finally, the studies rarely focused on individuals without a history of hypertension.

Use of NSAIDs may raise blood pressure through inhibition of production of vasodilatory prostaglandins,² sodium retention,³ or possibly increased endothelin 1 production.¹⁴ Because of its ready availability over the counter, ibuprofen is the most commonly used NSAID in this cohort (G.C.C., unpublished data, 1999). Our findings indicate that use of NSAIDs increases the risk of hypertension, even when taken infrequently. We did not detect significant interactions for NSAIDs with age, BMI, or family history of hypertension.

Little information is available in the literature regarding the effect of acetaminophen use on blood pressure. Short-term studies^9,15 have found no effect of acetaminophen use on blood pressure in treated hypertensive individuals. We did not find any case-control or prospective studies of the association between acetaminophen use and hypertension. Acetaminophen is a weak inhibitor of peripheral cyclooxygenase, but it may be a potent inhibitor of prostaglandin production in the central nervous system.¹⁶ In addition, acetaminophen use may inhibit nitric oxide production,⁵ which could lead to increased vascular tone and blood pressure. However, the mechanism for the increased risk of hypertension we observed is unknown.

Acute pain can lead to an increase in blood pressure by increasing sympathetic activity. However, scant information is available on the impact of chronic pain on blood pressure. Although chronic pain in frequent analgesic users could be a possible explanation for our findings, we would have expected an increased risk for all 3 analgesics; however, no association was observed for aspirin. It is possible that the underlying condition(s) (eg, rheumatoid arthritis) for which the participants took the analgesics is associated with an increased risk of hypertension, but we believe that this is unlikely. After we adjusted for self-reported rheumatoid arthritis, the RRs did not change. In addition, the increase in risk for NSAIDs and acetaminophen was significant at levels of use as low as 1 to 4 d/mo. This low frequency of use would be an unusual pattern for treatment of chronic pain. Finally, we would have expected similar risks for all 3 classes of analgesics.

Several limitations of this study should be addressed. This study was limited to women aged 31 to 50 years. We did not directly measure the participants' blood pressure, and the diagnosis of hypertension was self-reported. We do not have information on which women had blood pressure measured during follow-up. It is possible that women who were taking analgesics more frequently were more likely to visit a physician and have their blood pressure checked. However, we would have expected that this would have led to detection bias for any of the analgesics, yet no independent association was observed for aspirin use. In addition, when we limited the analysis to women who had at least 1 type of screening examination in 1995 and 1997, the results were essentially unchanged. The proportion of participants with missing information on frequency of use ranged from 7.9% for NSAIDs to 27.4% for aspirin. The characteristics listed in Table 1 did not differ substantially between those with and without missing information; however, it is possible that there were unrecognized factors that may be associated with frequency of analgesic use and with hypertension. Finally, as we do not have information on duration of analgesic use, it is unclear how long the medications need to be used before the risk begins to increase.

In conclusion, these findings indicate that use of NSAIDs and use of acetaminophen are associated with increased risk of hypertension but that aspirin use is not. A substantial proportion of hypertension in the United States, and the associated morbidity and mortality, may potentially be due to the use of NSAIDs and acetaminophen. Given that these medications are readily available over the counter and are used by a large proportion of the adult population, this association merits additional study.

Accepted for publication April 3, 2002.

This work was supported by grants DK52866, CA87969, and CA50385 from the National Institutes of Health, Bethesda, Md.

We thank the participants in the Nurses' Health Study and the Nurses' Health Study II and Sharon Curhan, MD, Elaine Coughlan, BS, Kris Vernon, Karen Corsano, BA, Gary Chase, BA, Julie Herbstman, BA, and Jennifer Atkinson, BA, for their contributions to this project.

Corresponding author and reprints: Gary C. Curhan, MD, ScD, Channing Laboratory, Brigham and Women's Hospital, 181 Longwood Ave, Boston, MA 02115 (e-mail: Gary.Curhan@channing.harvard.edu).