Opioid Analgesic Use and Risk for Invasive Pneumococcal Diseases

As opioid analgesic use has increased in the United States, the safety of prescription opioids has come under further scrutiny (14). Common safety concerns include the potential for opioid use disorders, overdose, and serious adverse respiratory and cardiovascular events (58). However, these known adverse effects only partially account for the excess morbidity and mortality observed among prescription opioid users (911). Although concern has been expressed regarding a potential excess of infections observed among prescription opioid users, few studies have attempted to quantify the risk for infection in this group (1214). Certain opioids have known immunosuppressive properties, and their use may increase the risk for infections (15, 16). Animal and in vitro experimental studies have demonstrated that some opioids disrupt lymphocyte and phagocyte proliferation, reduce innate immune cell activity, and inhibit cytokine expression and antibody production (1618). In animal models, opioid-induced immune disruption also led to increased susceptibility to bacterial infections, including those caused by common human pathogens, such as Streptococcus pneumoniae (1921). However, the clinical implications of these observations for humans, including whether the risk differs by specific opioid properties or dosage, remain unclear. Invasive pneumococcal disease (IPD), caused by S pneumoniae, includes serious illnesses, such as bacteremia, meningitis, and invasive pneumonia (22). The case-fatality rate for IPD is high among adults (pneumonia, 5% to 7%; bacteremia, 20%; meningitis, 22%) and thought to be even higher among older persons (23). Diagnosis of IPD requires the isolation of S pneumoniae from a normally sterile site (23). Known risk factors for IPD include age (young children and older adults are more susceptible), decreased immune function, chronic high-risk medical conditions (such as lung, liver, and kidney disease), and cigarette smoking (22, 2426). Because IPD monitoring and prevention remain a public health priority, and opioid analgesic use represents a potentially novel and modifiable risk factor for serious infectionsincluding IPDwe sought to test the hypothesis that opioid analgesic use is an independent risk factor for laboratory-confirmed IPD. Methods Data Sources We conducted a nested casecontrol study in a retrospective cohort of persons enrolled in TennCare, the managed Medicaid program in Tennessee. TennCare provides health care insurance to Tennessee residents who are Medicaid eligible. TennCare data provided information on enrollment, demographic characteristics, pharmacy use, health care encounters, and comorbid conditions for each participant. These data were supplemented with state vital records information and hospital-based data from the Tennessee Hospital Discharge Data System. Pharmacy data were supplemented with Medicare Part D information for dual-eligible participants. Laboratory-confirmed IPD cases were identified from the Tennessee Active Bacterial Core surveillance (ABCs) system. The ABCs system is funded by the Centers for Disease Control and Prevention to conduct active population- and laboratory-based surveillance in 10 states for disease due to selected pathogens of public health relevance, including IPD (27). In Tennessee, Vanderbilt University Medical Center collaborates with the Tennessee Department of Health and Tennessee Emerging Infections program to operate the ABCs system in 20 counties. The system collects demographic, health care encounter, risk factor, and specimen or pathogen information for every detected case. Institutional Review Board Approval This study was approved by the institutional review boards of Vanderbilt University Medical Center and the Tennessee Department of Health and of the Bureau of TennCare. Study Cohort All TennCare enrollees who had filled at least 1 study opioid prescription from 1995 to 2014 were identified (see Exposure) to exclude persons with contraindications to opioids and those who may not have been eligible to receive these drugs. The participants entered the study cohort on the earliest date (t0) that a study opioid prescription was filled. Inclusion criteria were continuous enrollment in TennCare for at least 365 days prior to t0, age 5 years or older, documented access to pharmacy benefits, more than 1 health care encounter and no IPD identified during baseline, and absence of nonstudy opioid prescriptions (see Exposure) during baseline or on t0. Participants also were required to have resided for at least 1 day during the study period in a Tennessee county that reported to the ABCs system (see CaseControl Selection). Follow-up continued from t0 through the earliest of the following: the end of the study (31 December 2014), death, loss of enrollment, IPD, or first nonstudy opioid use. Participants who ended follow-up because of loss of enrollment, IPD, or nonstudy opioid use were allowed to reenter the cohort if they subsequently fulfilled all eligibility criteria. CaseControl Selection We used the ABCs system to identify laboratory-confirmed IPD among cohort members. Invasive pneumococcal disease was defined by the isolation of S pneumoniae from a normally sterile site (such as blood or cerebrospinal fluid) (24). The sample collection date was the index date for each case. We used incidence density sampling to randomly select up to 20 cohort members at risk but without laboratory-confirmed IPD (control participants) per case patient. Control participants were matched to case patients by index date as well as by age (individual years) and county of residence on that date. A study participant could serve as a control participant for several case patients and could later become a case patient. Although nested casecontrol and cohort designs would provide the same conclusions, the former was preferred for efficiency, especially with regard to exposure and covariate classification. Classifications were done relative to the index date, which simplifies the extensive computational challenge of tracking time-varying exposure and covariate information throughout a traditional, long follow-up in a large cohort. Of importance, the nested casecontrol odds ratio (OR) provides an unbiased estimator of incidence rate ratios with negligible or no loss of precision (28, 29). Exposure The use of prescribed study opioids, either oral or transdermal, was the exposure of interest. Nonstudy opioids included antitussive and antidiarrheal agents (for nonpain indications); injectable formulations, for which timing of use and dosage may be difficult to ascertain; and drugs used primarily for opioid use disorders (such as buprenorphine). Using pharmacy data, we defined 4 mutually exclusive exposure categories relative to the index date for case patients and control participants. Current users were those with a study opioid prescription overlapping the index date. To minimize exposure misclassification due to imperfect adherence or intermittent use, recent users were those whose most recent prescription ended 1 to 90 days before the index date and past users were those whose most recent prescription ended 91 to 182 days before the index date. Remote users included persons in all other scenarios without an opioid prescription that ended within 182 days before the index date. New users were defined as a subset of current users whose prescription overlapping the index date was initiated after 182 days without an opioid prescription. Current opioid use, the main study exposure, was classified further according to the drug's duration of action (short or long), potency (moderate or high), previously described immunosuppressive properties (immunosuppressive, nonimmunosuppressive, or unknown), and estimated daily dose in morphine milligram equivalents (MME) on the index date (<50, 50 to 90, or ≥90 mg). Opioid characteristics were defined at the national drug classification code level of the agent on the basis of the previous literature and classifications used in earlier studies (Table 1) (7, 13, 14, 30). To avoid misclassification, current users of more than 1 opioid type were classified separately from those receiving only a single type. Table 1. Study Opioid Classifications* Covariates Relevant demographic characteristics, comorbid conditions (including IPD risk factors), conditions associated with pain, medication use, and health care use were measured during the 365 days before the index date and considered as potential confounders. Demographic characteristics included sex and race. Other covariates, including use of health care resources, were defined by using diagnosis and procedure codes. Well-recognized risk factors for IPD, according to the Advisory Committee on Immunization Practices, included alcohol or substance use disorder, cardiovascular disease, serious hepatic or chronic lung disease, end-stage renal disease or hemodialysis, HIV, cancer, immune disorders, diabetes, sickle cell disease, and tobacco smoking (25, 26). Other comorbid conditions included surrogate frailty markers (such as debility, pressure ulcers, and impaired mobility) (31). Conditions associated with pain included abdominal, back, musculoskeletal, dental, and neuropathic pain, as well as trauma or injury, headache, arthritis, and pain not otherwise specified. Health care use included nursing home residence and the baseline number of hospitalizations and outpatient and emergency department visits (Appendix Table 1). On the basis of our selection criteria, only persons with full benefits who demonstrated active use of those services were included. Thus, indicators for each study covariate were based on the presence of specific conditions and medication use. Lack of evidence meant the individual had no history of that condition or medication use, so this information was not considered missing. Appendix Table 1. Covariates Assessed in the 365 Days Preceding the Index Date Statistical Analysis