melanoma is a potentially fatal tumor that continues to increase in incidence despite public education measures to limit sun exposure . chemoprevention has been identified as an important strategy for reducing melanoma incidence . among the candidate agents , nonsteroidal anti - inflammatory drugs ( nsaids ) expression of cyclooxygenase-2 ( cox-2 ) , the primary pharmacologic target of nsaids , has been reported in up to 93% of melanomas . in addition , in vitro and animal studies have demonstrated a protective effect of nsaids against melanoma ; [ 46 ] however , studies in humans have had conflicting results [ 79 ] .   using a case - control design , we tested the hypothesis that nsaids convey a chemoprotective effect against melanoma . the genes , environment , and melanoma ( gem ) study is a multicenter case - control study investigating heredity and environment in melanoma . a full description of the gem study design has been published separately [ 1012 ] . in this report , only the university of michigan subjects were used , since supplemental data regarding medication usage was not collected from other centers . individuals with a first primary invasive melanoma diagnosed in the year 2000 and individuals with a second or higher order invasive primary melanoma diagnosed between january 1 , 2000 , and august 31 , 2003 , were eligible for participation . at the university of michigan site , the inclusion criteria for controls were a current spousal relationship to a melanoma subject and willingness to provide informed consent to participate . spouses were excluded from participation as controls if they had a personal history of melanoma . the current analysis is restricted to cases diagnosed with first primary invasive melanoma or melanoma in situ . the protocol was approved by the institutional review board at the university of michigan . subjects completed an interview assessing personal and family history of cancer , skin phenotype , medication use , and comorbidities . to assess past and current use of analgesics , they were asked to recall medications used on a daily basis for at least three months . contingency tables were used to assess the crude associations between medication use and melanoma risk . fisher 's exact test was used to determine p - values when cells contained counts of less than 10 . unconditional logistic regression was used to assess the association between medication use and melanoma risk , to adjust for confounding , and to identify any potential effect modification . potential variables evaluated for the multivariate model included age , gender , family history of melanoma , skin color , hair color , eye color , history of severe sunburn , history of cardiovascular disease , history of a musculoskeletal pain condition , tendency of skin to burn , tendency of skin to tan , age at first sunburn , number of moles on the back , smoking history , history of other medical diagnoses ( yes / no ) , and statin use . covariates were included in the initial multivariate model if the addition of that covariate to the univariate model of analgesic use and melanoma risk resulted in a 10% or greater change in the odds ratio . these covariates were then removed from the saturated multivariate model in a stepwise fashion to optimize the fit to the data as determined by the aic . seven hundred twenty - eight individuals were approached for study participation at the university of michigan . of these , 509 ( 69.8% ) completed the telephone interview . melanoma patients accounted for 390 of these subjects ; the remaining 119 were melanoma - free spouses of the patients . among the melanoma subjects , 104 had in situ melanoma , 223 had a first ( single primary ) melanoma , and 63 had a second or higher - order ( multiple primary ) melanoma . in this analysis , individuals with multiple primary melanomas were excluded , as we could not adjust for selection bias based on survival from the first primary melanoma . demographic characteristics are described in table 1 , and results are summarized in table 2 . due to the differences in gender and age between the melanoma and control groups , these variables were empirically included in the multivariate models . covariates in the final models were age , gender , skin color , family history of melanoma , and number of moles on the back . current or past use of aspirin was associated with an unadjusted odds ratio of 0.85 ( 95% ci 0.431.69 ) . the odds ratio was 1.45 ( 95% ci 0.444.74 ) in a multivariate model adjusted for age , gender , skin color , family history of melanoma , and number of moles . the number of moles had the most significant effect on the adjusted odds ratio . restricting the analysis to current users or those with invasive melanoma yielded similar results . due to small numbers of subjects , subjects with in situ melanoma were more likely to take aspirin than those with invasive disease , but this difference was not statistically significant ( or 0.615 ; 95% ci 0.291.31 ) . the unadjusted odds ratio for melanoma risk with any use of nonaspirin nsaids was 0.58 ( 95% ci 0.311.11 ) , and the adjusted odds ratio was 0.71 ( 95% ci 0.232.02 ) . covariates in the multivariate model were the same as in the aspirin model . the addition of aspirin use to the model did not affect the odds ratio , and results were similar when restricted to invasive melanoma . control subjects were more likely to be current users of nsaids ( or 0.45 ; 95% ci 0.230.88 ) ; however , this association was no longer significant when adjusted for covariates ( or 0.55 ; 95% ci 0.191.58 ) . nsaid use in subjects with in situ disease was similar to use in those with invasive melanoma . approximately 9% of controls reported regular use of cox-2 inhibitors . in an exploratory analysis , the crude odds ratio for melanoma in users of cox-2-inhibitors was 0.61 ( 95% ci 0.281.31 ) , and the adjusted odds ratio was 0.42 ( 95% ci 0.141.27 ) . in order to assess whether the effects of nsaids were due to the medical indication rather than the mechanism of action , we evaluated the effect of acetaminophen on melanoma risk . due to small numbers of users ( 2.5% of controls ) , fisher 's exact test was performed and yielded a two - sided p - value of  .72 . our results suggest that aspirin and nonaspirin nsaids are not associated with a durable large reduction in risk of melanoma once potential confounders are taken into account . a small beneficial effect of these medications may be seen in a larger study and can not be excluded . we were unable to fully assess the effects of cox-2 specific inhibitors or acetaminophen due to small numbers of regular users in our study . the first describes a case - control study of 110 women with melanoma and 609 matched controls . the relative risk of melanoma in women taking nsaids was 0.45 ( 95% ci 0.220.92 ) . our study builds on this result with the inclusion of men , an increased number of melanoma cases , and assessment of additional covariates . the second study investigated the effects of nsaids in individuals who had previously had melanoma . individuals taking cox inhibitors were less likely to have new primary melanoma , melanoma recurrence , or melanoma metastasis . our study takes this question from a secondary / tertiary prevention setting to a primary prevention setting . the third study linked nsaid use in the vitamins and lifestyle ( vital ) study to the nci surveillance , epidemiology , and end results registry . the number of cases in this study is similar to ours ; however , many had in situ rather than invasive melanomas . our study expands upon this result by using a larger number of invasive melanoma cases and adding data on number of moles , which was the most significant covariate in our analysis . the fourth study assessed this question in the dutch pharmo pharmacy database and the palga pathology database . they found a 46% reduction in melanoma risk for women who had continuous use of aspirin ( or 0.54 , 95% ci 0.300.99 ) . unfortunately , we could not validate reports of medication use with prescription records in our study , as many nsaids are dispensed over the counter , and use of these medications is not always accurately collected in the medical record . sun exposure could not be assessed as a potential confounder due to a lack of a simple , validated measure of this risk factor . however , we did evaluate self - reported history of severe sunburns , age at first sunburn , and tendency to burn as potential confounders ; these did not have a significant effect on the odds ratios . selection bias may be present in the control group , as not all spouses of melanoma subjects participated . data are not available on nonconsenting spouses , so we are unable to assess whether the participating spouses were representative of the potential control population as a whole . additionally , the odds ratios may be attenuated by overmatching of spouse controls , who may resemble the cases more than individuals in the general population . in summary , in our pilot study we found no significant association between analgesic use and melanoma risk when potential confounders are assessed . based on the conflicting data for this question , evaluation in a larger cohort that also allows for assessment of potential confounders or meta - analysis may be appropriate .
because nonsteroidal anti - inflammatory drugs ( nsaids ) inhibit tumor growth in vitro , we investigated the association between nsaids and melanoma to determine if there was epidemiologic evidence of a chemopreventive effect from these medications . three hundred twenty - seven subjects with incident melanoma and 119  melanoma - free controls completed a structured interview assessing melanoma risk factors . 
 the unadjusted odds ratio ( or ) for use of nonaspirin nsaids was 0.58 ( 95% ci 0.311.11 ) , in a comparison of subjects with melanoma to controls . 
 after adjustment for melanoma risk factors , the or was 0.71 ( 95% ci 0.232.02 ) . 
 aspirin users had an unadjusted or of 0.85 ( 95% ci 0.451.69 ) and an adjusted or of 1.45 ( 95% ci 0.444.74 ) .   in this pilot study , we found no evidence of a significant association between analgesic use and melanoma risk when potential confounders are assessed . based on conflicting reports in the literature 
 , meta - analysis may be appropriate .