The monthly MED was calculated for each patient on long-term opioid therapy and presented on a semi-logarithmic scale with projection histograms showing the distribution of MEDs and the cumulative time for which the patients were on opioids in the year before TKA (Fig. 4-A). The median MED was 832.5 mg/mo, with an interquartile range of 400 to 1,785 mg/mo. The median cumulative duration of opioid consumption in the long-term opioid therapy group was 10 months (interquartile range, 7 to 11 months). Figure 4-B depicts the distribution of the number of unique opioid formulations prescribed in the long-term opioid group; 67.2% (8,587) of the patients were prescribed >1 opioid formulation in that group. Following model selection and controlling for age, BMI, and clinically relevant comorbidities such as diabetes, depression, PTSD, congestive heart failure, and chronic kidney disease, a logistic regression model was fit with revision within 1 year and with revision at any time as dependent variables. We found that patients on long-term opioids before TKA were more likely to undergo revision within 12 months, with an odds ratio of 1.40 (95% CI, 1.19 to 1.64; p < 0.005). There was no difference in the likelihood of undergoing a knee manipulation between patients on long-term opioids and those not on long-term opioids. Table I shows the odds ratios for diabetes, long-term opioid use, and chronic kidney disease as markers for knee revision in the first year after TKA. Patients on long-term opioid therapy were more likely to undergo any knee revision during the study period, with an odds ratio of 1.28 (95% CI, 1.15 to 1.43). Table II shows the odds ratios for patients with diabetes, using opioids long-term, or with chronic kidney disease undergoing revision at any time. Older age was a protective factor in both models.
Survival curves for the time to revision within a year after TKA suggested that long-term opioid therapy in the year before surgery is associated with early knee revision following TKA (log-rank test, p < 0.05) (Fig. 5). There was no difference in the time to knee manipulation between the patients who were treated with long-term opioid therapy and those who were not (Fig. 6). The Cox proportional hazard model showed the relative risk of knee revision to be 19% higher in the long-term opioid group compared with the other group (Table III). Application of the machine-learning text classifier to the surgical notes on the revisions showed diabetes to be associated with revision for infection (chi square = 48.75, p < 0.05) but demonstrated no association between long-term use of opioids and the etiology of the revision.
This study demonstrated that long-term use of prescription opioids is highly prevalent among the (mostly) male population undergoing knee replacement surgery in the VA system. After controlling for relevant clinical features, we found that male VA patients on long-term opioid therapy had an increased hazard of, and odds ratio for, undergoing knee revision within a year after TKA. Long-term opioid use was not associated with any specific cause of the revision. In agreement with others, we found diabetes to be a risk factor for revision due to surgical site infection25,26, although diabetes did not play a significant role in the short term after TKA. Regarding obesity, our cohort had a substantial lack of weight and height data, which may have impacted the results; since we did not distinguish between revisions due to infection and those due to mechanical failure in our analysis, we cannot comment on a specific association between failure and obesity. Of note, a study of 70,070 patients did not show obesity to significantly increase the relative risk for revision27. In agreement with our finding, opioid use was not associated with knee manipulation following TKA in a large cohort of 27 million patients28.
To our knowledge, this is the first study to describe the prevalence of opioid prescriptions in the year prior to TKA in a large cohort of patients. In our group of >30,000 mostly male VA patients, we found an association between opioid prescription before TKA and the prevalence of early knee revision surgery. Of equal importance is the fact that about 40% of the patients were prescribed non-trivial amounts of opioids for about a year prior to TKA. Knee arthroplasty is one of the most common procedures performed in the U.S., and a report29 predicted an increased demand for both primary and revision TKA. In that report29, the authors used demographic data, historical surgical data, and life tables to predict that there would be 3.48 million knee arthroplasties by 2030 and that the number of knee revisions would double in the period of 2005 to 2030. Our study suggests that, in light of the current trend of liberal opioid prescription, including to individuals who will require knee arthroplasty, demographic projections of future trends in knee arthroplasty may need to include the effects of prescription opioid use. It is possible that a conservative policy for opioid prescription may reduce the rate of knee revisions, with an ensuing decrease in associated morbidity and costs.
Regarding the generalizability of this study, we used VA data on a national scale and our findings probably reflect VA practice. However, the majority of TKAs are done in females, and we cannot comment on differences in prescription patterns between the sexes given that our data were derived mostly from men. Replication of this study in more balanced populations will determine its generalizability.
Because the etiologies of the revisions had not been captured in a structured way in the records on our large cohort, we developed a machine-learning classifier to sift through the 1,422 postoperative notes of patients who had had at least 1 revision. This is an interesting demonstration of abstracting clinically meaningful data from unstructured text, and the fact that we found a significant association between diabetes and revision due to infection lends support to our methodology. Long-term opioid use was not associated with any specific cause of revision. This suggests that the mechanisms behind the association between revision and long-term opioid use might be related to behavioral differences and/or the sociopsychological environment of the long-term opioid users. The notion that a patient’s psychological state may affect surgical outcome has been studied34,35, although the effect of anxiety and depression needs to be quantified in a prospective investigation. Use of administrative databases to address a clinical question was a limitation of our study because the databases lacked clinically pertinent data (for example, preoperative and postoperative range of motion and knee severity scores). Because these parameters are important in the clinical assessment of patients preoperatively, looking at them in aggregate may allow us to better characterize patient populations. Nonetheless, large databases are a credible source of robust estimates and have aided both researchers and industry analysts in finding relevant information36.
Despite the limitations of our study, we believe that our observation that long-term use of opioids before TKA places patients at higher risk for an early revision holds true. We believe that future work should focus on (1) development of a decision support system that enables a physician discussing TKA with a patient to quantify the risk of an early revision, (2) replicating our findings in balanced populations and with data sets that include risk factors associated with success and failure of TKAs along with medication history, and (3) comparing the effects of liberal and conservative opioid prescription regimens on TKA outcomes in a prospective study.
A description of our method of classifying the causes of the revisions on the basis of the postoperative surgical notes is available with the online version of this article as a data supplement at jbjs.org.
NOTE: The authors thank Seth S. Leopold, MD, Department of Orthopaedics and Sports Medicine, University of Washington, for his insightful remarks, thorough reading of the manuscript, guidance, and substantial contribution in bringing this manuscript to its final form. They also thank the VA for lending the technical support in the execution of this study, especially Mr. William Carson from the Linux support team. Special thanks are extended to Ms. Rebecca Felkey for her assistance in editing the manuscript.
Investigation performed at the Department of Anesthesiology and Pain Medicine and Department of Orthopaedic Surgery and Sports Medicine, VA Puget Sound Health Care System, University of Washington, Seattle, Washington
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