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Opioids used for postoperative pain control after surgery have been associated with an increased risk of chronic opioid use. Hysterectomy is the most common major gynecological procedure in the United States; however, we lack a data-driven definition of new persistent opioid use specific to hysterectomy.The objectives of the study were as follows: (1) determine a data-driven definition of new persistent opioid use among opioid naïve women undergoing hysterectomy and (2) determine the prevalence of and risk factors for new persistent opioid use.We used data from Optum Clinformatics that include both medical and pharmacy data from a single national private health insurer. Hysterectomies performed from Jan. 1, 2011, to Dec. 31, 2014, were identified using current procedural terminology and International Classification of Diseases, ninth revision, codes. Inclusion criteria included the following: age ≤63 years at hysterectomy, no opioid fills for 8 months preceding (excluding the 30 days immediately prior), and no additional surgical procedures within 6 months after hysterectomy. The perioperative period was defined as 30 days prior to 14 days after hysterectomy. Number of opioid prescription fills, days supplied, and total oral morphine equivalents were analyzed to determine the distribution of opioid use in the perioperative and postoperative periods. We obtained demographics including age, race, educational level, and division of the country according to the US Census Bureau and used International Classification of Diseases, ninth revision, diagnosis codes to identify hysterectomy indications, surgical route, chronic pain disorders, depression/anxiety, and substance abuse. Bivariate analyses were used to compare persistent with nonpersistent opioid users. A hierarchical logistic regression model controlling for regional variation was used to determine factors associated with new persistent opioid use following hysterectomy.A total of 24,331 women were included in the analysis. New persistent opioid use was defined as follows: ≥2 opioid fills within 6 months of hysterectomy with ≥1 fill every 3 months and either total oral morphine equivalent ≥1150 or days supplied ≥39. Based on this definition, the prevalence of new persistent opioid use was 0.5% (n = 122). Median perioperative oral morphine equivalents prescribed to those who became new persistent users was 437.5 mg (interquartile range, 200–750) compared with 225 mg (interquartile range, 150–300) for nonpersistent users (P < .0001). Factors independently associated with new persistent opioid use included the following: increasing age (adjusted odds ratio, 1.04, 95% confidence interval, 1.01–1.06, P = .006), African-American race (reference: white, adjusted odds ratio, 1.61 95% confidence interval, 1.02–2.55, P = .04), gynecological malignancy (adjusted odds ratio, 7.61, 95% confidence interval, 3.35–17.27, P < .0001), abdominal route (adjusted odds ratio, 3.61, 95% confidence interval, 2.03–6.43, P < .0001), depression/anxiety (adjusted odds ratio, 2.62, 95% confidence interval, 1.71–4.02, P < .0001), and preoperative opioid fill (adjusted odds ratio, 2.76, 95% confidence interval, 1.87–4.07, P < .0001). The C-statistic for this model is 0.74.Based on our definition, the prevalence of new persistent opioid use among opioid-naïve women undergoing hysterectomy is low; however, 2 potentially modifiable risk factors are preoperative opioid prescription and abdominal route of surgery.