This present meta-analysis included 17 studies (8 cohort and 9 case-control studies), involving a total of 10,618 bladder cancer cases. In this meta-analysis of the 3 most commonly used analgesics and bladder cancer risk, we found that acetaminophen and aspirin were not associated with bladder cancer risk. Although non-aspirin NSAIDs was statistically significantly associated with reduced risk of bladder cancer among case-control studies (but not cohort studies), the overall risk was not statistically significant. Also, non-aspirin NSAIDs was significantly associated with a 43% reduction in bladder cancer risk among nonsmokers.
We found that acetaminophen use was not associated with the risk of bladder cancer with a pooled RR
1.01 from 10 studies. Acetaminophen is a metabolite of phenacetin, a well-known banned carcinogen which has been more so linked to renal pelvic tumor 
. Recently, a meta-analysis found that acetaminophen use was associated with 21% reduced risk of kidney cancer and the risk was higher with higher intake. In this meta-analysis, we did not found the associations of long term and high dose of acetaminophen use with bladder cancer risk.
In our meta-analysis, we did not found that aspirin use was associated with bladder cancer risk from 11 studies. Our results are in agreement with a large randomized controlled trial 
. In the Women’s Health Study, low dose aspirin (100 mg every other day) for an average of ten years did not lower bladder cancer incidence. And in the meta-analysis of aspirin and cancer risk, the pooled risk for bladder cancer was 0.95 (95% CI 0.83–1.07) 
We found from 6 studies that non-aspirin NSAIDs use was not associated with the risk of bladder cancer in general. Nevertheless, there was significant heterogeneity by study. After excluding the study by Sørensen et al 
, a significant inverse association was found. In this record linkage study from Denmark with 330 bladder cancer cases, prescribed non-aspirin NSAIDs slightly increased the risk of bladder cancer (RR 1.2; 95% CI, 1.0–1.3), although no dose-response relationship was observed. Misclassification is likely in studies relying solely on prescription data as many commonly used NSAIDs do not require a prescription. Therefore, due to the limited published information and relatively small number of cases, we still cannot draw the firm conclusion about non-aspirin NSAIDs use and bladder cancer risk. Further studies with a larger number of subjects may be able to discriminate the effects of specific NSAIDs more clearly.
Furthermore, an interest finding in our meta-analysis, although more limited, is that smoking status might modify the association of use of nonaspirin NSAIDs with bladder cancer risk. Smoking is a well-known risk factor for bladder cancer. There are over 60 carcinogens, including nitrosamines, aromatic amines, and polycyclic aromatic hydrocarbons, have been detected in cigarette smoke. Metabolic activation of these carcinogens leads to the formation of DNA adducts, causing miscoding and other mutations 
. While smokers have been shown to have increased cycloxygenase (COX)-2 expression and activity in their urothelial tissues 
, it may be that the anticarcinogenic effects of nonaspirin NSAIDs against COX-2 are overwhelmed by the carcinogenic effects of smoking. Thus, a decrease in bladder cancer risk associated with nonaspirin NSAIDs has been shown in nonsmokers in our meta-analysis.
Our study has several strengths: it is the most up-to-date comprehensive review of analgesics on one specific type of cancer, bladder cancer. It includes the 3 mostly used contemporary drugs and 17 observational studies were included in our meta-analysis, reporting data of more than 1 million participants, including 10,618 bladder cancer patients. Meta-analysis of studies with large numbers of incident cases provides high statistical power for estimating the relationship between exposure and outcome risk. Moreover, in a meta-analysis of published studies, publication bias could be of concern since small studies with null results tend not to be published. In this meta-analysis, however, we found little evidence of publication bias.
Nevertheless, several limitations are worth mentioning. First, a meta-analysis is not able to solve problems with confounding factors that could be inherent in the included studies. Inadequate control for confounders may bias the results in either direction, toward exaggeration or underestimation of risk estimates. However, most observational studies in this meta-analysis adjusted for other known and potential risk factors for bladder cancer. Second, heterogeneity may be introduced because of methodologic and demographic differences among studies. We used appropriate well-motivated inclusion criteria to maximize homogeneity, and performed sensitivity and subgroup analyses to investigate potential sources of heterogeneity. Third, studies used different definition of analgesic use, which might have limited comparability of the results across the studies. However, our findings were stable and robust in the subgroup analyses. Fourth, long-term analgesic users may switch the type of analgesics they use over time. Because almost all of the studies assessed analgesics use at baseline only, we were not able to evaluate the impact of change of use of analgesics. In addition, the study does not clearly distinguish between multiple exposures to analgesics. The possibility of confounding would be especially relevant for long duration users, as those patients could have used phenacetin many years previously. Last, because of lack of data, it was not possible to address the important issues of dose and duration of use needed to achieve effects.
In summary, the results of this meta-analysis of 17 observational studies indicated that use of acetaminophen, aspirin or non-aspirin NSAIDs was not associated with bladder cancer risk. However, non-aspirin NSAIDs use might be associated with a reduction in risk of bladder cancer for nonsmokers.