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Injection Alternatives for the Management of Knee Osteoarthritis Pain.

INTRODUCTION
There has been a rapid increase in opioid-related morbidity and mortality worldwide, and the dangers of excessive opioid use have been observed in patients with chronic musculoskeletal pain, including those diagnosed with knee osteoarthritis. Pain management is an important component of nonoperative treatment in knee osteoarthritis and frequently entails the use of opioids. However, this management technique is not without risks, such as addiction, morbidity, and mortality. Therefore, the purpose of this study was to review the existing literature on the use of opioids in the management of knee osteoarthritis and compare the findings to a new injection management modality. Specifically, we assessed: 1) trends in opioid prescription; 2) patient-reported outcomes; 3) incidence of complications; 4) incidence of abuse and dependence; and 5) mortality related to opioid use in knee osteoarthritis. We then performed a sub-analysis comparing these findings to TG-C, a novel a 3:1 mixture of genetically engineered chondrocytes that has shown promising early phase I, II, and III results.


MATERIALS AND METHODS
A literature search was performed utilizing the PubMed database with search terms including, but not limited to: "knee osteoarthritis," "total knee arthroplasty," "opioid," "annual trends," "outcomes," "complications," "dependence," "mortality," and "deaths". The initial search revealed 548 results, with an additional 182 sources added after reviewing associated references. After removing duplicates, 245 records were reviewed after which results were evaluated and stratified based on outcomes, yielding a total of 35 studies for final evaluation. Correlative and comparative analyses were performed evaluating trends in opioid prescription, patient-reported outcomes, incidence of complications, incidence of abuse and dependence, and mortality related to opioid use in knee osteoarthritis. Additionally, for each of the aims studied, a summative discussion relating study findings to clinical practice was performed. Outcomes from phase II and III trials of genetically engineered chondrocytes (GEC) injections were also analyzed with a focus on pain reduction.


RESULTS
Nearly all studies report markedly increasing trends in opioid prescriptions, with some studies showing significant incremental increases in prescription rates (31 vs. 40%) over time. Additionally, projection models predict-based on current rates of prescribing opioids-that by 2030, prescriptions will triple from 1.1 million in 2015 to 3.0 million in 2030. Along with this, mean oral morphine equivalent dosages will also increase by 22% over a 15-year period. When evaluating patient-reported outcomes, multiple studies have found no significant differences in patient-reported pain outcomes between opioid and non-opioid users (p>0.05). In fact, many studies even report poorer outcomes in patients who used opioids prior to surgical interventions. Opioid use was found to also be associated with increased referrals to pain management, longer in-hospital stays, and poorer Knee Society scores after total knee arthroplasty (TKA) (p<0.05). Furthermore, some studies report as high as 42% of patients continue to use opioids after the initial 90-day postoperative period, and epidemiologic data for the United States reveals an over 20x increase in opioid-related deaths from 0.3 to 6.2 per 100,000 between 1999 and 2016. Our sub-analysis revealed that GEC injections were found to significantly improve reductions in visual analog scale (VAS) pain (-37.2 vs. -23.4 mm, p<0.05) and International Knee Documentation Committee (IKDC) scores (23.0 vs. 12.7, p<0.05) between study and control cohorts, indicating this injection modality to potentially be a successful non-opioid based management technique that is safe and effective.


DISCUSSION
The effects of the opioid epidemic on patients with knee osteoarthritis are severe. Excessive opioid use in these patients leads to poorer patient satisfactions as well as increased morbidities and mortalities. Therefore, there is a real need for alternative nonoperative treatment options that effectively reduce pain, and promising results from studies on the efficacy GEC injections demonstrate that they may be an answer to the opioid epidemic observed among osteoarthritis patients.