In this study, we found that a substantial number of women who had mastectomy and reconstructive surgery became new, persistent users of controlled substances post-operatively. In terms of opioids, three in four opioid-naïve women filled a peri-operative opioid prescription, and 17.5% of these women became new persistent opioid users. While a smaller percentage of sedative-hypnotic naïve women filled a peri-operative sedative-hypnotic prescription (40%), these women went on to become new persistent sedative-hypnotic users at a comparable rate (17%) to those in the opioid cohort. Several demographic, clinical and economic variables were highly associated with the development of both new persistent opioid and sedative-hypnotic use: age less than 65, residence in the south, Medicaid insurance, breast cancer diagnosis and chemotherapy treatment. As the number of these risk factors increased in an individual patient, their risk of becoming a new persistent user increased as well.
Our study is novel in demonstrating an association between mastectomy and reconstructive surgery and the development of new persistent sedative-hypnotic use in a large, heterogenous population of women. Anxiety and insomnia are common in the breast cancer population, with persistent symptoms seen up to 1.5 years after curative surgery[14, 20]. Our findings suggest that a substantial number of women receive sedative-hypnotics for what may have been worsening anxiety and insomnia around the time of surgery, and a significant proportion of these women go on to use these agents chronically. While some of this use may be psychiatrically indicated, the concern is that a large amount may be unnecessary and preventable. Sedative-hypnotic misuse is an underrecognized public health problem in the general population[3, 25]. Our study suggests that women who have mastectomy and reconstructive surgery are susceptible to prolonged use of these medications, placing them at risk of future dependence on and misuse of these agents.
We found several factors to be particularly associated with the development of new persistent sedative-hypnotic use: age less than 65, chemotherapy treatment and Medicaid insurance. Sedative-hypnotic use and misuse is more common among those younger than 65 years of age in the general population[26–28], but to our knowledge this has not been well characterized in women undergoing breast cancer-related surgery[29]. Chemotherapy use generally reflects higher risk disease, and high rates of consequent anxiety and insomnia among these patients may render them particularly susceptible to sedative-hypnotic dependence. Additionally, sedative-hypnotics are frequently used to treat chemotherapy-related nausea[30]. Our findings suggest that a sedative-hypnotic prescription intended for the management of chemotherapy-related symptoms can put patients at risk of becoming persistent users. Finally, Medicaid insurance has previously been associated with persistent opioid use post-operatively[31]. Our study corroborates this finding in the mastectomy and reconstruction population, and additionally finds an association between Medicaid insurance and post-surgical sedative-hypnotic dependence.
We also found that a prior mental health diagnosis was not predictive of the development of new persistent sedative-hypnotic use. Women with pre-existing anxiety or mood disorders in our study cohorts were not previously managed with sedative-hypnotic medications, as patients filling prescriptions between 365 to 31 days prior to surgery were excluded from our analysis. It is possible that patients who were excluded increased use, however we were not able to study that in the current analysis.
Rates of sedative-hypnotic use and misuse in women with breast cancer have only been previously studied to a limited degree[7, 32]. One recent study assessed benzodiazepine use in elderly patients with breast cancer undergoing curative intent treatment using SEER-Medicare data[29]. The authors found that 111 of 955 benzodiazepine-naïve patients received and continued to fill prescriptions up to 3 months post-operatively. However, this study only assessed an older cohort of patients over a short duration of follow up. Our study defines mastectomy and reconstructive surgery as a concrete, generalizable risk factor for the development of new persistent sedative-hypnotic use up to one year post-operatively.
The association between mastectomy and reconstructive surgery and new persistent opioid use has been demonstrated previously[21, 22]. Marcusa et al. (2017) found that among 4,113 opioid-naïve patients undergoing mastectomy and reconstruction over a four-year period, 10% continued to fill prescriptions for opioids up to 4 months post-operatively. Our study builds on these findings by examining a substantially larger cohort of opioid-naïve women (25,270 vs. 4,113) over a longer period of follow-up (12 months vs. 4 months). We were also more conservative in our definition of new persistent use, requiring patients to fill at least two prescriptions in the post-operative period in order to receive this designation.
An additional finding of note in our study is the high rate of overlap in controlled substance exposures. We found that 70.9% of new persistent opioid users filled a sedative-hypnotic prescription during the study period as well, while 98.2% of new persistent sedative-hypnotic users filled an opioid prescription. Sedative-hypnotics are known to potentiate the respiratory depressive effects of opioids[33], and concomitant opioid and sedative-hypnotic use has been associated with increased rates of long-term opioid use, opioid overdose and all-cause mortality[34–37]. In particular, pre-operative sedative-hypnotic use among opioid-naïve patients increases the risk of long-term opioid use post-operatively[38]. Patients prescribed both categories of controlled substances around the time of mastectomy and reconstruction should receive particular attention, as they may be at even high risk of long-term use and subsequent complications.
Our study has several limitations. We were only able to determine that prescriptions were filled by patients, not what the indication was for prescribing or whether patients actually took the medications. Additionally, we did not control for surgical complications or receipt of additional procedures after the index procedure. This could account for some of the opioid use seen during period 3, but is less likely to affect the sedative-hypnotic findings. Finally, we did not have information on potentially relevant sociodemographic characteristics, such as race and ethnicity, and certain medical details, such as cancer stage and chemotherapy regimen. As such, our risk summary scores are somewhat simplistic due to these limitations. While MarketScan is a rich database, there are limitations to the socioeconomic and medical variables that we can control for in building predictive models using this data.
Our results suggest that women are susceptible to becoming new persistent users of both opioid and sedative-hypnotic medications after mastectomy and reconstructive surgery, with certain variables significantly and additively increasing their risk. Patients and providers should be aware of this important potential complication and attempt to limit use when appropriate. Providers should pay particular attention to patients receiving prescriptions for both opioid and sedative-hypnotics, as this overlap may render patients at increased risk for long-term use of one or both medication classes. Pharmacologic and non-pharmacologic strategies may help patients manage pain and anxiety after cancer-related surgery, and specific interventions may help patients use controlled substances safely and effectively[39].