Long-term Health Outcomes of New Persistent Opioid Use After Gastrointestinal Cancer Surgery

As the number of annual opioid overdose-related deaths in the United States continues to rise, curbing opioid misuse remains a persistent public health crisis.^1,2 Notably, perioperative opioid use has been identified as a major contributor to the current opioid epidemic because more than 35% of all opioid prescriptions are for perioperative use.²³ In turn, perioperative opioids function as a potential gateway for continued opioid misuse when patients consistently request refills beyond the anticipated time frame for pain resolution, resulting in NPOU.¹⁶ Notably, patients undergoing oncologic procedures may be vulnerable to the development of NPOU, as they are commonly prescribed higher doses of opioids for extended periods.²⁴

Nonetheless, the incidence and long-term health care outcomes of NPOU among patients undergoing gastrointestinal cancer surgery remain ill-defined. Therefore, the current study was important because it addressed this significant literature gap by using nationally representative data to evaluate long-term clinical outcomes among patients who experienced NPOU after gastrointestinal cancer surgery. Notably, NPOU was associated with higher morbidity and mortality because the odds of hospital or emergency department visits related to falls, respiratory symptoms, or pain increased by 45%. Moreover, patients who experienced NPOU had more than a twofold increase in the risk of death 1 year after surgery.

Perioperative pain control is a crucial aspect of surgical care, and patients typically receive opioids only for short-term breakthrough pain control.²⁵ Nonetheless, prior studies have reported that patients may continue using opioids beyond the intended duration.^13,26 As such, NPOU use has been increasingly recognized as a common postoperative complication.^13,26 For instance, Roberts et al.²⁶ studied elderly female patients undergoing breast cancer surgery and reported that 2.8% of the patients experienced NPOU postoperatively. Similarly, Brummett et al.¹³ reported an NPOU incidence of 6.5% after major surgery, similar to the 6.3% incidence rate noted in the current study. Notably, the incidence of NPOU in our cohort was higher than that reported for patients who underwent surgery for breast cancer.²⁶ This difference may have been attributable to the aggressive nature of gastrointestinal cancers, which often require extensive surgery and pain control with higher doses of opioids for an extended duration, thereby increasing the risk for the development of NPOU.²⁷

Importantly, the current study highlighted that individuals with a history of substance abuse, Medicaid eligibility, or high social vulnerability were at a higher risk for the development of NPOU. Notably, these individuals may face several social, health, and economic stressors that contribute to NPOU.^28,29 Specifically, individuals residing in areas with high SVI have poor health literacy, inadequate access to health care facilities, and multiple comorbid conditions requiring pain control that can result in continued opioid use even when not medically necessary.^28,29 Consequently, NPOU is a common event among vulnerable patients undergoing high-risk surgery for a malignant indication. Therefore, before prescribing opioids, clinicians must screen for social risk factors that may contribute to the development of postoperative NPOU. In turn, referral to appropriate counseling services may be necessary to highlight the potential dangers associated with prolonged use of opioids and reduce the risk of NPOU.

Persistent use of opioids contributes to an additional health care burden, with greater health care use and expenditures in the postoperative period.^12,30 Prior studies have demonstrated that perioperative opioid prescription carries a dose-dependent risk of falls and related injuries, especially in the elderly population.²⁰ Additionally, patients with continuous opioid use after surgery are at risk of respiratory depression and other respiratory complications.³¹ Similarly, the current study noted that Medicare beneficiaries with NPOU had 45% greater odds of hospital or emergency department visits due to falls, pain symptoms, or respiratory events than individuals without NPOU. These findings were in line with a study by Santosa et al.¹² that observed a similar pattern of increased hospital visits due to pain among patients with NPOU after common general surgical procedures.

Although opioids are commonly used as painkillers, there is a lack of evidence demonstrating their long-term effectiveness.³² Opioid-induced hyperalgesia during the acute perioperative period is well-documented, and more recently, this phenomenon has been observed among individuals with prolonged opioid exposure.^32,33 In the current study, the reasons for frequent hospital visits due to pain among the patients with NPOU were likely multifactorial, although opioid-induced hyperalgesia may have played an important role.³⁴ Importantly, the current data also demonstrated that the patients with NPOU were associated with a greater risk of mortality 1 year after surgery. This finding may have been attributable to several underlying risk factors and may not have been solely due to NPOU. For example, the patients who experienced NPOU were more likely to have a history of prior substance abuse (other than opioids), to reside in areas with greater socioeconomic vulnerability, and to present with late-stage disease. These factors have been associated previously with poor postoperative outcomes and a higher risk of mortality.^35‐37 Nonetheless, the patients with NPOU did face an elevated risk of confounder-adjusted 1 year mortality. Taken together, these factors show that NPOU poses a major health care challenge that necessitates prompt and effective interventions to alleviate the extensive health care burden on patients with gastrointestinal cancer.

The results of the current study underscore the importance of preoperative risk stratification and comprehensive perioperative pain management plans to prevent NPOU. In the preoperative setting, patients should be screened for NPOU risk factors, and if opioids are prescribed, close monitoring is needed.³⁸ For instance, the Toronto General Hospital introduced transitional pain services to identify patients at risk for opioid misuse and decrease the risk of misuse through education, the development of a personalized pain management plan, and close follow-up evaluation for weeks to months after surgery.³⁹ Moreover, in the postoperative period, surgical pain may be managed through multimodal analgesia, with a focus on non-opioid medications such as acetaminophen, non-steroidal anti-inflammatory drugs, gabapentin, and ketamine.^40‐42 In fact, a combination of non-opioid analgesics can provide equivalent pain relief among patients with cancer.⁴³ Furthermore, Razi et al.⁴⁴ reported that an enhanced recovery after surgery (ERAS) protocol was beneficial in reducing inpatient opioid requirements and the subsequent development of NPOU among patients with lung cancer.

There is a need for opioid stewardship programs that focus on prescription monitoring, patient education, and health care provider training.⁴⁰ In line with this, the Massachusetts General Hospital implemented several multidisciplinary interventions, including opioid guidelines for common surgical procedures, health care provider-focused posters in all surgical units, patient opioid awareness brochures, and educational seminars for residents, nurses, and advanced practice providers.⁴⁵ As a result, opioid prescription doses decreased significantly without the need for refills.⁴⁵

In general, preventing morbidity and mortality associated with NPOU requires a multifaceted approach.⁴⁰ This approach should encompass cancer-specific opioid prescription guidelines, multimodal analgesia, frequent monitoring, increased awareness among patients regarding opioids, and health care provider education.⁴⁰

The current study should be interpreted considering several limitations. The use of a large national database in the study was a notable strength. However, the retrospective design and dependence on an administrative database introduced the potential for residual confounding bias. Additionally, administrative datasets may be subject to coding errors and inaccurate data input. The study sample consisted of patients 65 years of age or older with Medicare coverage, which may have limited the generalizability of the results to younger patients and those with private insurance. Substance use disorders and mental health conditions are generally underreported in the SEER database. Therefore, beneficiaries identified with a substance use disorder or mental health condition may not be a true representation of the general population. Furthermore, SEER-Medicare data may have inadequate sensitivity to measure substance abuse and mental health disorders. Due to database limitations, a granular assessment of other painful conditions and mood disorders (e.g., severity of impairment or symptoms) that may be driving persistent use could not be examined. Medicare data do not provide details about the reason for opioid prescriptions. Moreover, pharmacy claims data provide information only on opioid fills, whereas patients may fill opioid prescriptions but choose not to use them. Prospective data are needed for a better understanding of specific patient-level risk factors and underlying causes associated with the development of NPOU.

In conclusion, 1 in 15 patients undergoing surgery for gastrointestinal cancer experienced NPOU postoperatively. As an additional health care burden, NPOU is associated with a greater likelihood of mortality and hospital visits due to falls, respiratory complications, and pain symptoms. These findings underscore the importance of preoperative screening, patient opioid awareness, use of non-opioid analgesics, and close monitoring of opioid prescriptions in the postoperative period.