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American Journal of Epidemiology Advance Access published online on April 4, 2008
American Journal of Epidemiology, doi:10.1093/aje/kwn082
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American Journal of Epidemiology © The Author 2008. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

ORIGINAL CONTRIBUTION

Analgesic Drug Use and Risk of Epithelial Ovarian Cancer

Charlotte G. Hannibal1,2, Mary Anne Rossing1,3, Kristine G. Wicklund1 and Kara L. Cushing-Haugen1

1 Program in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, WA
2 Department of Viruses, Hormones, and Cancer, Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark
3 Department of Epidemiology, School of Public Health and Community Medicine, University of Washington, Seattle, WA

Correspondence to Dr. Mary Anne Rossing, Program in Epidemiology, Fred Hutchinson Cancer Research Center, P.O. Box 19024 (M4-C308), Seattle, WA 98108-1024 (e-mail: mrossing{at}fhcrc.org).

Received for publication December 17, 2007. Accepted for publication March 11, 2008.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Analgesic use may reduce ovarian cancer risk, possibly through antiinflammatory or antigonadotropic effects. The authors conducted a population-based, case-control study in Washington State that included 812 women aged 35–74 years who were diagnosed with epithelial ovarian cancer between 2002 and 2005 and 1,313 controls. Use of analgesics, excluding use within the previous year, was assessed via in-person interviews. Logistic regression was used to calculate odds ratios and 95% confidence intervals. Overall, acetaminophen and aspirin were associated with weakly increased risks of ovarian cancer. These associations were stronger after more than 10 years of use (acetaminophen: odds ratio (OR) = 1.8, 95% confidence interval (CI): 1.3, 2.6; aspirin: OR = 1.6, 95% CI: 1.1, 2.2) and were present for indications of headache, menstrual pain, and other pain/injury. Reduced risk was observed among aspirin users who began regular use within the previous 5 years (OR = 0.6, 95% CI: 0.4, 1.0) or used this drug for prevention of heart disease (OR = 0.7, 95% CI: 0.5, 1.0). These results, in the context of prior findings, do not provide compelling evidence of a true increase in risk of ovarian cancer among women who use these drugs. However, they add to the weight of evidence that, in the aggregate, provides little support for the use of analgesic drugs as chemoprevention for this disease.

acetaminophen; anti-inflammatory agents, nonsteroidal; aspirin; ovarian neoplasms

Abbreviations: CI, confidence interval; NSAID, nonsteroidal antiinflammatory drug; OR, odds ratio


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Inflammation has been suggested to be involved in the etiology of ovarian cancer, possibly acting in concert with ovulation (1, 2). Medications with antiinflammatory properties, such as aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs), have been proposed as potential agents for the chemoprevention of ovarian cancer (3). Acetaminophen, on the other hand, has weak antiinflammatory activity but may reduce risk through an antigonadotropic effect (4).

Available data regarding the relation of ovarian cancer risk to analgesic drug use are inconsistent. Only a subset of studies has examined use of these drugs over the lifetime, and almost no studies have examined whether the reasons the drugs were taken might influence the associations observed. In a population-based, case-control study of epithelial ovarian cancer, we assessed the risk associated with use of analgesic drugs, with a focus on characterizing risk associated with these aspects of exposure.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
The study population and methods have been described previously (5). Briefly, the study was conducted in a 13-county area of western Washington State covered by the Cancer Surveillance System, a population-based registry that is part of the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute. Cases were English-speaking women, 35–74 years of age, who were diagnosed with a primary invasive or borderline epithelial ovarian tumor between January 1, 2002, and December 31, 2005. Of the 1,058 women eligible, 812 were interviewed (76.7 percent); of the interviewed women, 595 had invasive disease.

Controls were selected by random digit dialing (6, 7) using stratified sampling in 5-year age categories, 1-year calendar intervals, and two county strata in a 2:1 ratio to women with invasive epithelial ovarian cancer. For 14,561 (82.0 percent) of the 17,768 telephone numbers belonging to residences, we determined whether an eligible woman (i.e., an age- and county-eligible woman able to communicate in English and, if so, with at least one ovary and no prior history of ovarian cancer) resided there. Of the 1,561 eligible women identified, 1,313 were interviewed (84.1 percent), for an overall (screening x interview) response proportion of 69 percent.

The study was approved by the local institutional review board, and all women provided signed, informed consent before participating. In-person interviews were conducted from 2002 through 2006 and pertained to the time before diagnosis (for cases) or an assigned, comparable reference date (for controls). The interview covered the following: demographic and lifestyle characteristics; family and personal history of cancer; detailed reproductive history; and medical history, including analgesic drug use. Women were asked to recall prescription and nonprescription medications taken over their lifetime for pain, inflammation, or disease prevention. A show card with the generic and common brand names of analgesic drugs, including acetaminophen, aspirin, ibuprofen, naproxen, and other NSAIDs, was provided as a memory aid. Women were first asked if they had ever taken any of these medications 5 or more days per month for at least 6 consecutive months; women who indicated that they had not used at least this minimal level of analgesic drugs were considered never users in our analyses. Women who responded affirmatively were asked the name of each drug taken for 6 months or more, the number of days per month taken (recorded as categories of 5–7, 8–14, and >14 days but less than daily, daily, or almost daily), and the month and year of starting and either discontinuing or changing the monthly frequency of use. For each episode, we recorded the primary reason for using the drug and grouped these as headache, menstrual pain, injury or pain other than menstrual cramps, heart disease prevention, or other reasons.

Using unconditional logistic regression, we calculated odds ratios as estimates of the relative risk and related 95 percent confidence intervals of epithelial ovarian cancer associated with various aspects of analgesic drug use while controlling for the confounding effects of other variables. All analyses were adjusted for the frequency matching variables of age (5-year intervals), county of residence (dichotomized as the three urban or the 10 rural/suburban counties in the study), and calendar year of diagnosis/reference date (continuous), as well as the number of full-term pregnancies (0, 1, 2, ≥3) and duration of hormonal contraception (<6, 6–59, 60–119, or ≥120 months). Additional adjustment for other potential confounding variables, including race/ethnicity, education, age at menarche, body mass index, smoking, alcohol, family history of breast and ovarian cancer, personal history of breast cancer, hysterectomy, tubal ligation, unilateral oophorectomy, and use of menopausal hormone therapy, produced no important change in the odds ratio estimates.

For our primary analyses, women who had never used any analgesic drugs on a regular basis (as defined above) served as the referent group. To reduce the possibility that symptoms of an ovarian cancer that had not yet been diagnosed might have influenced use of analgesic drugs, we excluded use that occurred within the year before the diagnosis/reference date. Risk was assessed separately among the subgroups of women who had used acetaminophen, aspirin, and ibuprofen, as well as among the combined group of women who had used any type of NSAID (including aspirin and nonaspirin NSAIDs but not acetaminophen). In analyses of daily use of analgesic drugs, the duration assessed included only the time periods in which the drug was taken on a daily basis; that is, time periods when use was less than daily were not included. We also examined epithelial ovarian cancer risk in women whose regular analgesic use was restricted to either acetaminophen or aspirin. Finally, we examined the use of acetaminophen and aspirin according to the primary reason the drug was taken. When a woman had used one of these drugs for more than one indication (grouped as headache, menstrual pain, other pain or injury, or cardiovascular disease) over the course of her lifetime, duration of use of the drug for each indication was considered separately.

We repeated our analyses separately among case groups of women with borderline and invasive epithelial ovarian tumors and in histologic subgroups (i.e., serous, mucinous, endometrioid, clear cell, and other epithelial tumors); we also examined risks separately among women less than 55 and 55 or more years of age. All analyses were carried out using the STATA, version 9.2, statistical package (StataCorp LP, College Station, Texas).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
Cases were more likely than controls to be nulliparous, to have a body mass index at age 30 years of 30 kg/m2 or more, and to have a family history of ovarian cancer; they were less likely to have used hormonal contraceptives or to have had a tubal ligation (table 1). In total, 1,007 women (47 percent) reported having used one or more of acetaminophen, aspirin, ibuprofen, or other NSAIDs at a frequency/duration of 5 or more days per month for at least 6 consecutive months, more than 1 year before the reference date. Aspirin (controls: 22.2 percent), ibuprofen (controls: 18.5 percent), and acetaminophen (controls: 16.4 percent) were the most commonly reported analgesics, whereas naproxen (controls: 6.3 percent), cyclooxygenase-2 inhibitors (controls: 4.3 percent), and other nonsteroidal analgesics (controls: 1.8 percent) were taken by a smaller number of women.


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  		TABLE 1. Characteristics of epithelial ovarian cancer cases and controls, western Washington State, 2002–2005

 
Compared with women who had never used analgesic drugs, users of acetaminophen, aspirin, or any NSAID (including aspirin) were at a slightly increased risk of epithelial ovarian cancer (table 2). Increased risk occurred primarily in women who had used these drugs for more than 10 years, among whom the odds ratios were 1.8 (95 percent confidence interval (CI): 1.3, 2.6) and 1.6 (95 percent CI: 1.1, 2.2) for acetaminophen and aspirin, respectively, with a somewhat lesser increase in risk associated with more than 10 years' use of any type of NSAID (odds ratio (OR) = 1.3, 95 percent CI: 1.0, 1.7). Among women who used acetaminophen or aspirin for more than 20 years, the risk was more than doubled (acetaminophen: OR = 2.5, 95 percent CI: 1.5, 4.0; aspirin: OR = 2.1, 95 percent CI: 1.3, 3.4 (data not shown)). We observed no clear association of duration or other aspects of ibuprofen use with risk of epithelial ovarian cancer (results not shown). Other types of NSAIDs were reported too infrequently to allow a separate examination.


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  		TABLE 2. Risk of epithelial ovarian cancer in relation to self-reported lifetime use (to 1 year before diagnosis/reference date) of acetaminophen, aspirin, and NSAIDs,* western Washington State, 2002–2005

 
Increased risks were also observed among women who began using acetaminophen or aspirin at an earlier age or in the more distant past, characteristics which were linked with long duration of use. For both acetaminophen and aspirin, increases in risk were also more evident among women who had discontinued use 5 or more years before the reference date than among women who had used these drugs more recently. Risk increases noted among women who used any type of NSAID were generally weak and were largely driven by the use of aspirin. Among aspirin users, women who initiated regular use less than 5 years before the reference date were at a reduced risk (OR = 0.6, 95 percent CI: 0.4, 1.0).

Regular use of more than one type of analgesic was common among both cases and controls. For example, 383 women were users of acetaminophen, of whom 166 women (43 percent) also used aspirin. Because increases in risk were observed among users of both of these drugs, we assessed associations with risk among women who reported regular use of only aspirin or only acetaminophen (table 3). Although the patterns of risk observed were broadly similar to our overall findings (e.g., ORs associated with >10 years of acetaminophen and aspirin use were 1.7 (95 percent CI: 0.9, 3.3) and 1.3 (95 percent CI: 0.8, 2.2), respectively), these analyses lacked precision because of the smaller numbers of women included. In an alternative analysis (data not shown), we compared acetaminophen users with never users of acetaminophen and aspirin users with never users of any NSAID, which allowed adjustment of each drug for (duration of) use of the other. With this approach, the adjusted odds ratios for more than 10 years' duration of use of acetaminophen and aspirin were 1.7 (95 percent CI: 1.2, 2.4) and 1.4 (95 percent CI: 1.0, 2.0), respectively.


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  		TABLE 3. Risk of epithelial ovarian cancer in relation to self-reported lifetime use (to 1 year before diagnosis/reference date) of acetaminophen and aspirin, among women who used only acetaminophen or aspirin, western Washington State, 2002–2005

 
Women used analgesics for a variety of indications. Headache was the most commonly reported reason for regular use and long-term (>10 years') use of acetaminophen as well as long-term use of aspirin, while prevention of cardiovascular disease was the most common reason given for regular aspirin use (table 4). Use of acetaminophen or aspirin, particularly for more than 10 years, was associated with an increased ovarian cancer risk among women whose reason for use was headache, menstrual pain, or other pain or injury. Small numbers of women who used analgesics for particular indications limited the statistical precision of some estimates, particularly for menstrual pain. Aspirin, but not acetaminophen, was used for heart disease prevention; among women who used aspirin for this purpose, the risk was reduced (OR = 0.7, 95 percent CI: 0.5, 1.0).


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  		TABLE 4. Risk of epithelial ovarian cancer in relation to self-reported lifetime use (to 1 year before diagnosis/reference date) of acetaminophen and aspirin by reason for drug use,* western Washington State, 2002–2005

 
Overall, 155 acetaminophen users (40 percent), 294 aspirin users (61 percent), and 593 NSAID users (61 percent) were identified as daily users (data not shown). For acetaminophen, associations with risk among daily users (relative to never users of analgesic drugs) were very similar to the overall results (e.g., OR for >10 years' duration of daily use = 1.8, 95 percent CI: 1.0, 3.3). For aspirin, the association with more than 10 years' duration of daily use was somewhat reduced relative to the overall results (OR = 1.3, 95 percent CI: 0.8, 2.1), reflecting the reduced risk associated with aspirin used for prevention of heart disease and the tendency for aspirin used for this indication to be taken on a daily basis.

Our results were similar in analyses that separately considered borderline and invasive tumors (data not shown), and no clear differences in risk were observed across categories of histologic types (data not shown). Moreover, risk estimates were similar among women aged less than 55 and 55 or more years.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
Our study has several strengths, including a population-based design, a relatively large study size, and a relatively high prevalence of regular use of analgesics. However, our finding of an increased risk among women who had used aspirin or acetaminophen for more than 10 years was unexpected and in the opposite direction of what was hypothesized, and chance or bias must be considered as an explanation of our results. It is possible that reporting of analgesic use may have been influenced by the presence of ovarian cancer symptoms in case women. We attempted to reduce the impact of this potential bias by truncating our assessment of exposure (for both cases and controls) 1 year before the diagnosis/reference date. Because an increased risk occurred primarily among long-term users of acetaminophen and aspirin, the presence of cancer symptoms leading to use of analgesics before diagnosis seems unlikely to explain those findings.

In addition, women who agreed to participate may have had a prevalence of prior analgesic use that was not representative of the source population of our study. To influence our findings, such selective participation would have had to occur to a different extent among controls than cases. Although we adjusted our results for factors that are strongly linked with ovarian cancer risk (parity and hormonal contraceptive history) and found little evidence of confounding by these or other covariates, it is nevertheless possible that confounding by unknown or unmeasured characteristics linked with analgesic use and ovarian cancer risk may influence our results.

We attempted to collect detailed information about lifetime history of analgesic drug use, using both generic and brand names of these products as memory aids. However, several features of analgesic drug use influence the accuracy with which this exposure can be ascertained. Analgesics are widely available under multiple brand and generic names, and switching between types of analgesics may be both common and difficult to report. Some formulations contain combinations of analgesics (e.g., acetaminophen and aspirin) as well as other drugs (e.g., antihistamines and caffeine). In addition, some degree of exposure to analgesics over the lifetime is nearly ubiquitous, and it is not known what extent (frequency, duration, or recency) of exposure can be recalled with reasonable accuracy. Inaccuracies may also occur in recall or reporting of indication for use, particularly among women who had multiple reasons for regular use over the lifetime. Finally, although analyses of daily use may offer advantages related to increased accuracy of recall and/or extent of exposure, the exclusion of nondaily use (or, alternatively, inclusion of nondaily users in the unexposed group), as well as the tendency for use for cardiovascular disease prevention to be both daily and of lower dose, may impact study findings in ways that are difficult to predict.

Multiple observational studies of analgesic drug use and the risk of ovarian cancer incidence or mortality have been conducted (3, 4, 8–18), and most of these have been included in several recent reviews and meta-analyses (19–22). Generally, most individual studies have reported either moderate-to-weak risk reductions among users of some types of analgesics or no alteration in risk. The summary reviews and meta-analyses have reached various conclusions that range from no effect of aspirin or nonaspirin NSAIDs (20) to a weak risk reduction among users of acetaminophen (22) or aspirin (21) to a 47 percent reduction in risk among daily users of aspirin (19). Bosetti et al. (21) reported less evidence of an effect of analgesic use in cohort than in case-control studies, for example: relative risks of 0.98 (95 percent CI: 0.80, 1.20) and 0.82 (95 percent CI: 0.69, 0.99; pheterogeneity = 0.07) among aspirin users in cohort and case-control studies, respectively. The meta-analyses conducted by Bonovas et al. (20, 22) noted some evidence for publication bias in the results for aspirin but not NSAIDs or acetaminophen. The only randomized trial that investigated aspirin use in relation to ovarian cancer found no association (relative risk = 0.95, 95 percent CI: 0.68, 1.35), with an intervention of low-dose (100 mg) aspirin taken every other day for an average of 10 years' duration (23). Moreover, prior observational studies that assessed analgesic use for 10 years or more generally did not observe clear associations of ovarian cancer risk with this aspect of exposure, nor was there any suggestion that risk might be particularly increased among long-term users (3, 4, 8, 9, 22).

Although the design and analytical strategies of the various studies examining analgesic use and ovarian cancer risk differ in multiple ways, none of these differences readily accounts for the divergent results of the current and prior studies. As in the current study, several previous studies truncated their assessment of analgesic drug use (in at least some analyses) 1 year prior to the diagnosis or reference date (4, 11–14, 16), whereas others did not (3, 8–10, 15, 17). Some studies considered only over-the-counter (4) or only prescription (11, 14, 18) analgesics, while other studies (including the current study) assessed use of both (10). Several studies, similar to our own, defined regular drug use as use over the lifetime for one of the following: at least once a week for 6 consecutive months (4, 8, 12, 15); at least three times a week for 6 consecutive months (16); or at least once a week for 1 year (13). Other studies ascertained less than lifetime use (e.g., cohort studies that assessed use starting at the baseline and/or follow-up interviews (3, 9) and a case-control study that assessed use within the last 5 years (10)) or used record linkage to pharmacy databases (11, 14, 18).

Our results changed little when we accounted for the use of aspirin among users of acetaminophen or vice versa, either by restriction of our analyses to women who reported use of only one or the other of these drugs or by adjustment. In addition, our findings concerning daily use of acetaminophen, aspirin, and NSAIDs did not differ markedly from our overall findings. When we conducted separate analyses of invasive and borderline tumors or of histologic subtypes of tumors, we noted no clear differences in risk within these subgroups, and risks were similar among women less than 55 and those 55 or more years of age.

To our knowledge, the hospital-based study of Tavani et al. (15) is the only previous study that assessed the risk associated with different indications for analgesic use and considered only aspirin. They reported a slight reduction in risk among women who used aspirin for cardiovascular disease prevention (OR = 0.79, 95 percent CI: 0.33, 1.90) and no association with aspirin used for pain relief (OR = 1.06, 95 percent CI: 0.52, 2.17), although these estimates were relatively imprecise. In the current study, we observed a reduction in risk only among women whose regular aspirin use had begun relatively recently (within the last 5 years) or who used aspirin for the prevention of heart disease. Overall, our results provide little evidence of a reduced risk of developing epithelial ovarian cancer after regular use of acetaminophen, aspirin, or NSAIDs, particularly when these drugs were used for relief of pain or inflammation.

Despite the elevated odds ratios that we observed among long-term users of aspirin and acetaminophen in the current study, our results, in the context of the results of prior studies, do not provide compelling evidence of a true increase in risk of ovarian cancer among women who use these drugs. However, they add to the weight of evidence that, in the aggregate, provides little support for the use of analgesic drugs as chemoprevention for this disease.


   ACKNOWLEDGMENTS
 
Funding for this work was provided by the National Institutes of Health (grant RO1 CA87538).

The authors thank Dr. Noel Weiss for his comments on the manuscript.

Conflict of interest: none declared.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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