Ibuprofen use was significantly associated with a lower risk of developing PD. The combined multivariate RR of PD was 0.62 (95% confidence interval [CI] 0.42–0.93; p = 0.02); in contrast, no significant associations were observed for uses of aspirin, other NSAIDs, or acetaminophen (figure 1; table e-1). In the dose-response analysis, more tablets of ibuprofen use, but not aspirin or acetaminophen, were associated with lower risk of PD (p for trend = 0.01) (table 2). Further adjustment for self-reported gout, use of other individual types of analgesics, sleep duration, bowel movement, and use of antidepressants did not materially change these results.

This association remained in all sensitivity analyses. The multivariate RR for ibuprofen use was 0.64 (95% CI 0.43–0.96) after excluding patients with gout, and 0.63 (95% CI 0.39–1.01) after excluding patients with PD identified within 2 years of the follow-up. Excluding ibuprofen use reported 2 years prior to onset of PD generated similar results (multivariate RR = 0.65; 95% CI 0.43–0.99; p = 0.04). Compared with nonusers, the RR was 1.00 (95% CI 0.73–1.38) for users with 2–4 years of cumulative ibuprofen use, 0.74 (95% CI 0.24–2.29) for 6–8 years, and 0.43 (95% CI 0.15–1.28) for 10 or more years. A similar association between ibuprofen and PD risk remained in analyses including PD cases not confirmed by treating physicians or review of medical record (RR = 0.62; 95% CI 0.42–0.91). There were no significant interactions between use of any analgesics and age, smoking, or caffeine intake.

We identified a total of 12 published studies that had examined the association between NSAIDs use and PD risk (table e-2).^3,4,15,–23 Six studies were excluded because of retrospective data collection^15,17,22 or not differentiating nonaspirin NSAIDs from aspirin.^16,18,21 The remaining 6 studies^3,4,19,20,23 were then included in the meta-analysis with the current one, including a total of 2,779 PD cases. The pooled RR was 0.73 (95% CI 0.63–0.85; p < 0.0001) for ibuprofen use (figure 2 A) and 1.12 (95% CI 1.01–1.23, p = 0.03) (figure 2B) for aspirin use. Use of other NSAIDs or acetaminophen was not associated with PD risk (figure 2, C and D). We identified no significant heterogeneity (p > 0.20 for all) nor evidence of publication bias (p > 0.3 for the Begg and Egger tests) among these studies.

Strengths of this study include its large sample size and high follow-up rate. Because we included only incident PD cases, our results are unlikely to be significantly affected by recall or selection bias. Further, our assessment of NSAID use was previously shown to be reliable (see appendix e-1) and intended to cover both prescription and over-the-counter uses. Studies based on prescription records^16,18,19,21 may have had exposure misclassification as ibuprofen is primarily used over the counter in both the United States and Europe. For example, in the third US National Health and Nutrition Examination Survey (1988–1994), 29.7% of US adults reported monthly use of ibuprofen, as compared to only 1.9% prescription use.²⁴ A few limitations of the current study should also be considered. The reproducibility of NSAIDs use was assessed in the NHS, but not in the HPFS. NSAID use was self-reported and thus subject to error; however, because of the prospective design, this error would most likely be nondifferential with respect to the future risk of PD, and thus would tend to attenuate the underlying association between NSAID use and PD. The validity of exposure assessment was supported by previous findings from these cohorts on other chronic diseases for which the associations of NSAIDs were consistent with their pharmacologic effects.^25,26 Our cohorts do not represent random samples of US men and women; therefore, the patterns of use of NSAIDs cannot be taken to reflect the general population. Nevertheless, the biological effects of ibuprofen on PD in these cohorts should be the same as those among men and women in general, as suggested by the results obtained from the meta-analysis.

Accumulating postmortem and experimental evidence suggests that inflammatory mechanisms may contribute to the progressive loss of dopaminergic neurons in the substantia nigra of the brain.^1,2 Concentrations of several proinflammatory cytokines were elevated in the brain and CSF of patients with PD and also in prediagnostic blood samples of patients with PD.^1,2 While neuroinflammation may have some beneficial effects, uncontrolled inflammatory reactions may contribute to a self-perpetuating cycle that eventually leads to the degeneration of dopaminergic neurons.^27,28 Experimentally, several NSAIDs alleviate the loss of dopaminergic neurons but the effect of individual drugs is inconsistent across parkinsonian models, and the underlying mechanisms remain uncertain.^27,29 NSAIDs may confer benefit by inhibiting cyclooxygenase (COX), scavenging reactive oxygen and nitrite radicals, or inhibiting the activation of TNFα.^29,30 Some NSAIDs, such as ibuprofen and indomethacin, can also activate the peroxisome proliferator-activated receptor γ (PPARγ) pathway.^27,29,30 Further, NSAIDs use was examined in relation to PD in several epidemiologic studies.⁵ However, the finding that ibuprofen use, but not use of aspirin or other NSAIDs, was associated with lower PD risk suggests mechanisms other than a generic anti-inflammatory activity of NSAIDs.

NSAIDs are a heterogeneous group of compounds with different structures and pharmacologic properties.²⁷ Because the neuroprotective effects of individual compounds rank differently across parkinsonian models, no specific NSAIDs emerge from experimental studies as an unequivocal neuroprotectant for PD. However, in inflammatory and oxidative stress models of PD, ibuprofen can display protective properties not shared by aspirin or other NSAIDs.^31,32 Ibuprofen acts as a ligand for PPARγ, a novel therapeutic target for PD.^29,30 PPARγ can inhibit apoptosis and oxidative damage and counteract the activity of NF-κB, Ap-1, of the signal transducer and activator of transcription-1, and of the nuclear factor of activated T cells.³³ In a recent animal study, ibuprofen, but not aspirin, significantly attenuated the reduction of PPARγ expression and dopamine transporter–positive signals, and controlled the accumulation of activated microglial cells induced by methamphetamine.³¹ Further, in the MPTP mouse model, ibuprofen dose-dependently alleviated the loss of striatal dopamine without toxicity to dopaminergic neurons, while some other NSAIDs (e.g., indomethacin) appeared to be toxic at high doses.³⁴ Interestingly, the dose equivalency for ibuprofen:naproxen in CNS (10:1) is much higher than in peripheral inflammatory assays (10:7), although the mechanisms underlying this difference remain unclear.³⁵ Further support for a potential neuroprotective effect of ibuprofen comes from epidemiologic studies of dementia, where long-term use of ibuprofen, among several individual commonly used NSAIDs, was most strongly associated with a reduced risk of AD.³⁶ Experimental studies also showed that ibuprofen, but not aspirin, naproxen, or celecoxib, lowered β-amyloid 42 levels, a main culprit in the AD pathogenesis.³⁷

Two alternative interpretations of our results should be also considered. The first is confounding by indication: the possibility that ibuprofen was used to treat conditions that themselves are associated with lower PD risk. However, the primary reason for ibuprofen use was muscle/joint pain (accounting for 84% use in our previous study³⁸) and there is no evidence that these symptoms are associated with lower risk of PD. On the contrary, because pathologically confirmed cases of PD commonly present with or are preceded by painful musculoskeletal symptoms,³⁹ one might have actually expected an increased risk of PD in those taking ibuprofen, suggesting that the observed reduced risk of PD among ibuprofen users may have been underestimated. Further, we showed similar results after excluding participants with gout, a condition which could be associated with both ibuprofen use and PD. The other alternative explanation is that individuals at high risk of PD have a more stoic personality,⁴⁰ and are thus less likely to use analgesics. This personality hypothesis, however, was based primarily on anecdotal clinical observations and would not easily explain why only ibuprofen use, but not use of other analgesics, was associated with a lower risk of PD.