Opioid Analgesics and the Risk of Serious Infections Among Patients With Rheumatoid Arthritis: A Self‐Controlled Case Series Study

Abstract

Objective Animal and in vitro studies suggest that certain opioid analgesics impair crucial immune functions. We sought to determine if opioid use is associated with an increased risk of serious infections in patients with rheumatoid arthritis (RA). Methods We conducted a self-controlled case series analysis on a retrospective cohort of 13,796 patients with RA enrolled in Tennessee Medicaid (1995–2009). We performed within-person comparisons of the risk of hospitalizations for serious infections during periods of opioid use compared with non-use using conditional Poisson regression. Fixed confounders were accounted for by design, and time-varying confounders included age, the use of disease-modifying anti-rheumatic drugs, glucocorticoids and proton-pump inhibitors. Additional analyses examined new opioid use, use of opioids known to have immunosuppressive properties, long acting opioid use, and different opioid dosages. Sensitivity analyses accounted for potential protopathic bias and confounding by indication. Results Among 1,790 patients with RA who had at least one hospitalization for serious infection, the adjusted incidence rate of serious infection was higher during periods of current opioid use compared with non-use [incidence rate ratio (IRR): 1.39 (95% confidence interval (CI): 1.19–1.62)]. The incidence rate was also higher during periods of long-acting opioid use, immunosuppressive opioid use and new opioid use compared with non-use [IRR: 2.01 (95% CI: 1.52–2.66); IRR: 1.72 (95% CI: 1.33–2.23); IRR: 2.38 (95% CI: 1.65–3.42), respectively]. Results of sensitivity analyses were consistent with the main findings. Conclusions In within-person comparisons of patients with RA, opioid use was associated with an increased risk of hospitalizations for serious infection.

The Use of Prescribed Opioid Analgesics & the Risk of Serious Infections

“…A case-control study conducted among older adults enrolled in a private health insurance system reported a 39% increased odds of current opioid exposure among pneumonia cases compared with controls [18]. Similarly, in a study conducted among patients with rheumatoid arthritis enrolled in a State Medicaid program, periods of current opioid use were associated with a 38% increased risk of serious infections (including pneumonia, bacteremia, meningitis/encephalitis, septic arthritis/osteomyelitis, endocarditis, pyelonephritis and cellulitis) compared with periods of non-opioid use [19]. More recently, a nested case-control study, conducted in a population of subjects aged 5 years or older enrolled in a State Medicaid program, reported a 62% higher risk of laboratory-confirmed invasive pneumococcal disease among current users of opioids compared with past users [20].…”

“…Importantly, each of these studies consistently reported that patients using long-acting and high potency opioid formulations, opioids at high doses and opioids previously described as exhibiting immunosuppressive properties (i.e., morphine, codeine, fentanyl and methadone) had the highest risk for infection. The studies also noted a high risk for infections among patients recently initiating opioid use [18][19][20].…”

“…Opioid use was associated with an increased risk of multiple infection types across the three studies, demonstrating that the association cannot be fully explained by other opioid-related mechanisms which could contribute to infection (i.e., opioid-induced respiratory depression and microaspiration leading to pneumonia) [18][19][20]. Furthermore, each study applied strategies to account for potential protopathic bias (i.e., the possibility that individuals initiated opioid use to treat early symptoms of infection) and confounding by indication (i.e., individuals received opioids for an indication that is a risk factor for infection itself ) [18][19][20].…”

“…Furthermore, each study applied strategies to account for potential protopathic bias (i.e., the possibility that individuals initiated opioid use to treat early symptoms of infection) and confounding by indication (i.e., individuals received opioids for an indication that is a risk factor for infection itself ) [18][19][20]. In addition, in the study that examined the association between opioid use and the risk of laboratory-confirmed invasive pneumococcal disease, an extensive sensitivity analysis showed that residual confounding would be unlikely to explain the observed association [20].…”

Hospital-Treated Pneumonia Associated with Opioid Use Among Community Dwellers with Alzheimer’s Disease

“…Previous research has associated opioid use with a higher risk of pneumonia in different population groups [13][14][15][16][17]. However, the risk of pneumonia among opioid users with cognitive disorders has not been studied previously.…”