SLR - May 2021 - Yen Tran

Risk of Nonunion with Nonselective NSAIDs, COX-2 Inhibitors, and Opioids 

Reference: George M, Baker J, Leonard C, Mehta S, Miano T, Hennessy S. Risk of Nonunion with Nonselective NSAIDs, COX-2 Inhibitors, and Opioids. The Journal of Bone and Joint Surgery. 2020 Jul 15;102:1230-8. 

Level of Evidence: Level III - Therapeutic

Scientific Literature Review

Reviewed By: Yen Tran, DPM
Residency Program: AMITA Health St. Joseph Hospital – Chicago, IL

Podiatric Relevance: This study compared the nonunion rates in three groups of pain medication in fracture healing. The three groups were nonselective NSAID, COX-2 inhibitors, and opioids. COX-2 inhibitors were found to have the highest rate of nonunion, followed by opioids, then nonselective NSAIDs. This is important when considering pain management in fracture healing. 

Methods: The data used was from Optum from January 1, 2000 to September 30, 2015. Patient selection included >18 year old, inpatient or outpatient, 1 long fracture per patient in lower or upper extremities or clavicle, >6 months baseline enrollment, >1 year of continuous follow up. Patients were excluded if they had multiple fractures or had prior diagnose of nonunion or malunion. The data categorized patients based on pain medications prescriptions for nonselective NSAIDs, selective COX-2 inhibitors, and/or opioids 90 days before or after the fracture date. The diagnosis code selected was for nonunion (733.82) from 91 to 365 days after the initial fracture diagnosis with a procedure to treat nonunion (surgery, bone grafting, electrical non stimulation) within 30 days after the diagnosis of nonunion or if there were nonunion without procedure. Other variables that were analyzed included age, sex, geographical region, year, filled prescriptions for glucocorticoids or anticoagulants, energy of the injury, fracture location, open versus closed, initial treatment, location and patient comorbidities. 

Results: Filling a nonselective NSAID prescription following fracture showed no increased risk of nonunion after adjusted data analysis (nonunion adjusted odds ratio = 1.09, nonunion plus procedure = 1.07). Filling a COX-2 inhibitors and opioids prescription showed increased risk of nonunion (COX-2 inhibitors nonunion =1.84, nonunion plus procedure = 1.48; Opioid nonunion = 1.69, nonunion plus procedure = 2.05).

Filling a nonselective NSAID and COX-2 inhibitors prescriptions 90 days prior to fracture showed increased risk of nonunion (NSAID nonunion = 1.44, nonunion plus procedure = 1.36; COX-2 inhibitors nonunion = 1.60, nonunion plus procedure = 1.76). Filling an opioid prescription 90 days before the fracture was not associated with an increased risk of a nonunion diagnosis plus procedure =1.04 but was modestly associated with a nonunion diagnosis = 1.09. Other variables analyzed showed no significant differences.

Conclusions: This study concluded that nonselective NSAID prescription fills following a fracture was not associated with an increased risk of nonunion but COX-2 inhibitor and opioid prescription fills following a fracture were associated with increased risk of nonunion. However, the effect of nonselective NSAID should be further studied before coming to a conclusion. There may be confounding factors such as dosage and duration that may have an impact on fracture healing, hence the study found that there is a higher risk of nonunion in patients who fill the NSAID prescription 90 days prior to fracture. It was also found that opioids prescription fills were associated with increased risk of nonunion but it could be that patients who filled for opioids had higher-energy injuries and thus innately higher risk of nonunion. Adjustments in the data is unlikely to completely account for the confounding variables. 

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