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Long-term painkiller use linked to cancer risk

Tuesday 13 September 2011

“Painkillers triple the risk of kidney cancer,” reported the Daily Express. It said that taking non-steroidal anti-inflammatory drugs (such as ibuprofen) for 10 years tripled the risk of renal cell cancer, the most common kidney cancer.

This research pooled data from two large studies of 77,525 women and 49,403 men for up to 20 years, during which time 333 people developed kidney cancer. Those who regularly took non-aspirin NSAIDs (defined as taking one type of painkiller two or more times a week) were 51% more likely to develop this type of kidney cancer than non-regular users. There was also an association between the number of years of use and the risk of renal cell cancer, with more than 10 years of regular use tripling the risk.

The news reports could have benefited from pointing out that renal cell cancer is relatively rare and, in the groups studied here, less than 0.3% developed it during the 20-year follow-up period. As such, though this was a large study, only a small number developed kidney cancer. This increases the uncertainty about the accuracy of these risk estimates. This is a particular problem in this study because the cancer cases were further divided into how frequently they used NSAIDs. For example, the reported tripling in risk applied to people who regularly used NSAIDs for more than 10 years and this group included only 19 of the cancer cases. As such the tripled risk figure should be interpreted with caution.

This study appears to show an increase in risk of kidney cancer with non-aspirin NSAID use. It is important to point out that the link was only significant if the drugs were taken regularly for a long time. It is also important to put these findings in perspective for the individual, and highlight that the absolute risk of kidney cancer is low. However, in light of the widespread use of NSAIDs, this is an important finding requiring further study and follow-up. 

Where did the story come from?

The study was carried out by researchers from Harvard Medical School and Brigham Women’s Hospital. Funding was provided by the US National Institutes of Health, the Kidney Cancer Association and the Dana-Farber/ Harvard Cancer Center Kidney Cancer Specialized Programs of Research Excellence.

The study was published in the peer-reviewed journal Archives of Internal Medicine .

The Daily Express and the Daily Mirror gave adequate top-level coverage of this research. Both reports would have benefited from highlighting that although there was a tripling in risk for taking these drugs for more than 10 years, the absolute risk remained low.

The Daily Express described how many people were in the cohorts and the number of people who went on to have renal cell cancer. However, neither newspaper emphasised that as only a small number of people developed renal cell cancer in this study, the risk estimates are likely to be less accurate than if more cases had been studied.

What kind of research was this?

This was an analysis of two prospective cohort studies aimed at investigating whether there was an association between painkiller use and the most common type of kidney cancer - renal cell cancer.

The researchers say that painkillers are the most commonly used drugs in the USA, and that some studies have demonstrated potential health benefits from aspirin and painkillers such as ibuprofen and other non-steroidal anti-inflammatory drugs (NSAIDS) including protection from cardiovascular disease and bowel (colorectal) cancer.

However, they say that some population data have shown that painkiller use may also be associated with an increased risk of developing renal cell cancer. These predominantly case-control studies compared lifestyle and other factors between people who had renal cell cancer and people who did not. Unfortunately, these previous studies were small, assessing fewer than 100 people with renal cell cancer, and had only short follow-up.

In this study the researchers wanted to analyse data from prospective cohort studies so that they could follow people who didn’t have kidney cancer over time to try to determine factors that were associated with the development of kidney cancer. By looking at data from two cohorts they had, in total, data from more than 170,000 people.

What did the research involve?

The two cohorts in the study were the Nurses’ Health Study (NHS), which enrolled 121,700 female nurses aged 30 to 55 years in 1976, and the Health Professionals Follow–up Study (HPFS), which enrolled 51,529 male health professionals aged between 40 and 75 in 1986.

Every two years the cohort participants were sent a questionnaire asking them about lifestyle factors, including their use of painkillers. The NHS study started to ask about aspirin use in 1980, but only started to ask about non-aspirin painkillers in 1990. For this reason the researchers started their current analysis from 1990 onwards so that they could look at all types of painkillers. They started their analysis of the HPFS from its start in 1986.

The researchers collected information on dosage (number of tablets taken per week) and investigated the reasons why people took painkillers by questioning a sample of 200 women in the NHS in 1990. In 1999 an extra questionnaire was also sent to a sample of 4,238 nurses in the NHS study, again asking why people took painkillers and what type of NSAID they used.

To maintain consistency across the cohorts and with previous studies, the researchers defined regular painkiller users as those who took one type of painkiller two or more times a week.

Using the data collected from the cohorts the researchers also assessed other risk factors for renal cell cancer. These included smoking, weight (BMI), how physically active the person was and history of high blood pressure. In every two-year questionnaire the participants were asked about whether they had been diagnosed with cancer. If the participants reported kidney cancer (or the next-of-kin for participants who had passed away), the researchers asked permission to look at their medical records to determine which type of kidney cancer they had.

What were the basic results?

The follow-up period was up to 16 years among the 77,525 women in the NHS study and up to 20 years among the 49,403 men. In total there were 333 cases of renal cell cancer - 153 of these were women and 180 men.

The most frequently taken painkiller was aspirin. Other drugs taken by the women who took aspirin were non-aspirin NSAIDS (12%), paracetamol (10%) and both medications (4%). In men, 6% took aspirin and non-aspirin NSAIDs, 8% took aspirin and paracetamol, and 1% took aspirin, non-aspirin NSAIDs and paracetamol.

Women and men who regularly took painkillers were more likely to be past smokers and to have a history of high blood pressure.

The researchers found that the use of aspirin or paracetamol was not associated with renal cell cancer risk. Regular use of non-aspirin NSAIDs at the start of the study was associated with an increased risk. Compared with non-regular use of these painkillers, frequent use was associated with a 51% increased risk (Relative Risk [RR] 1.51; 95% Confidence Interval 1.12 to 2.04).

The researchers then looked at the risks associated with duration of use. For people regularly using non-aspirin NSAIDS:

  • for less than four years there was no increased risk compared with non-regular users (RR 0.81, 95% CI 0.59 to 1.11)
  • for four to ten years there was no increased risk compared with non-regular users (RR 1.36, 95% CI 0.98 to 1.89)
  • for more than 10 years, there was an almost three times increased risk compared with non-regular users (RR 2.92, 95% CI, 1.71 to 5.01)

Finally, the researchers carried out an analysis of whether there was a dose-dependent relationship between non-aspirin NSAID use and risk of renal cell cancer. This showed a statistically significant trend for increasing risk with increasing duration of frequent use of non-aspirin NSAIDs.

How did the researchers interpret the results?

The researchers said that “longer duration of use of non-aspirin NSAIDs may increase the risk of renal cell cancer”. They also said “risk and benefits should be considered in deciding whether to use analgesics; if our findings are confirmed an increased risk of renal cell cancer should be considered”.


This pooled analysis of two large cohorts has demonstrated an association between frequent use of non-aspirin NSAIDs and an increased risk of a type of kidney cancer called renal cell carcinoma. Two strengths of this study were its large size and that it prospectively followed participants for a long time. A large cohort was important as the incidence of renal cell cancer is relatively low (about 0.26% of the pooled cohort developed it).

However, the small number of cases is likely to decrease the accuracy of these risk estimates, particularly when the cases are further divided by how frequently they used NSAIDs. For example, though a tripled risk of renal cell cancer was found for people who used NSAIDs regularly for more than 10 years compared with people not using them regularly, only 14 people with renal cell cancer had used NSAIDs for this period of time. Therefore, risk calculations involving such small numbers should be interpreted with some caution.

The researchers noted several other potential limitations to their study. They said that although they took into account some potential confounding factors, there could have been some that they did not adjust for. For example, they said that patients with renal cell cancer may have started to take the painkillers before being diagnosed with the cancer to treat the symptoms. However, they said that as the largest association was found in people who had been taking the non-aspirin NSAID for a long duration, it is unlikely that this potential confounder influenced the results.

This study followed two North American cohorts from the late eighties. The most frequently used and most available non-aspirin NSAIDs may be different from those that are used in the UK. The researchers said that they have only recently started to collect more detailed information on the dose of NSAIDs, but as yet the follow-up from this subsequent investigation is not long enough to provide more information on the possible relationship between non-aspirin NSAIDs and renal cell cancer risk. They say that with longer follow-up, they would be able to give more detail on the dose-response relationship between non-aspirin NSAIDs and renal cell cancer risk.

Despite these limitations, this study highlights a potential risk of frequent, long-term use of non-aspirin NSAIDs relative to non-frequent long-term use. Although it should be emphasised that the absolute risk of developing renal cell cancer is small, as NSAIDs are very widely used, any risks, however small, warrant further study. This study is likely to highlight to doctors the importance of weighing up the potential risks and benefits when prescribing different types of painkillers for people who have chronic conditions, but should not concern people who use non-aspirin NSAIDS in the short term.

Analysis by Bazian
Edited by NHS Website

Links to the headlines

Painkillers triple the risk of kidney cancer.

Daily Express, 13 September 2011

Painkillers triple the risk of kidney cancer.

Daily Mirror, 13 September 2011

Links to the science

Cho E, Curhan G, Hankinson SE, et al.

Prospective evaluation of analgesic use and risk of renal cell cancer.

Archives of Internal Medicine 2011;171:1487-1493

Further reading

Johansen KL.

Renal cell carcinoma and the widespread use of NSAIDs.

Editorial. Archives of Internal Medicine 2011; 171: 1493