The association between perioperative opioids and breast cancer recurrence: a narrative review of the literature

Introduction

Background

Opioids have been a cornerstone for perioperative and postoperative pain management in cancer patients for centuries. In the late 1990’s, pharmaceutical industries developed extended-release opioids, marketed them as non-addictive, and a rise in opioid use disorder and associated deaths followed (1). The widespread opioid crisis has been an impetus for the development of multimodal analgesia protocols for perioperative pain management, and a culture shift towards more judicious opioid prescribing is underway. However, the coronavirus disease 2019 (COVID-19) pandemic brought obstacles to outpatient care, increasing isolation, and disrupting opioid use disorder treatment, which placed susceptible individuals at greater risk for overdose (2). Additionally, the decrease in non-emergent hospital visits caused a decline in pain management alternatives, pushing the vulnerable towards increased demand for prescription opioids.

Rationale and knowledge gap

According to the American Cancer Society, breast cancer is the most common cancer in women in the United States, accounting for about 30% of all new female cancers yearly (3). Breast cancer surgery, specifically, simple mastectomy with reconstruction, is among the highest-risk surgeries associated with chronic opioid use. Almost 20% of patients continue to fill opioid prescriptions 180 days after surgery and nearly 10% were still filing their prescriptions up to 1 year after surgery (4). The majority of postoperative opioids are prescribed by the operating surgeon or the perioperative care team (5,6). However, most prescribed opioids go unused, creating a reservoir of opioids available for diversion (7). Outside of the well-known untoward effects such as nausea, constipation, sedation, respiratory depression, and risk of dependence, preclinical studies have reported a link between opioids, cancer growth, and metastasis (8). Perioperative opioid minimization strategies can mitigate these risks.

Objective

Our objective is to investigate the association between perioperative and postoperative opioid use and oncologic outcomes. While similar reviews have been published, we aim to delve deeper by creating a distinction between local and distant recurrence, differentiating the timing of opioid and nonopioid analgesia, and the route of administration. With the increasing incidence of breast cancer, the high rate of opioid use disorder after breast cancer surgery, and the potentially tumorigenic effects of these opioids published in the referenced preclinical literature (9), the review will highlight the available evidence of the association between opioid minimization and potential for recurrence. We present this article in accordance with the Narrative Review reporting checklist (available at https://tbcr.amegroups.org/article/view/10.21037/tbcr-23-6/rc).

Methods

A narrative review was conducted to identify clinical associations between perioperative opioid use and breast cancer recurrence or metastasis. Due to the broad scope of the clinical and translational components of the concept, a narrative review format was selected to explore the literature. The search strategy is summarized in Table 1. From November 1, 2021, to November 30, 2021, the Ovid and EMBASE databases were searched from inception to November 2021 using a combination of the terms: breast neoplasm, opioid analgesics, neoplasm recurrence, and neoplasm metastasis. The initial search resulted in 350 publications. A flowchart of the study selection is provided in Figure 1.

Figure 1 Flow chart of initial articles retrieved and inclusion process.

The 350 publications were screened by a single reviewer via title and abstract for relevance. Studies that were not clinical and did not address breast cancer, opioid use, and recurrence or metastasis were excluded, as were non-English reports and duplicate articles. Additional included works were identified by a manual search of the reference lists of the retrieved articles that met the inclusion criteria. A single author critically appraised the final 38 studies via a full-text analysis, and the relevance of each article was then discussed with a second reviewer to reach a consensus for inclusion. From this 38, articles were excluded due to duplication or lack of clinical evaluation of human breast cancer metastasis or recurrence with opioids. If no dual consensus was achieved, the article was excluded. A total of 11 clinical studies were included in the present review (Table 2).

Results

Clinical studies of opioids’ impact on local recurrence demonstrate mixed results

Most of the referenced studies found no strong association between opioids and breast cancer recurrence. Three studies paradoxically found lower recurrence in cohorts receiving more opioids. Lee et al. compared recurrence-free survival for modified radical mastectomy (MRM) patients between propofol-based total intravenous anesthesia (TIVA) or sevoflurane-based anesthesia. In this study, recurrence sites were bone, brain, lung, chest wall, or liver. TIVA patients had higher intraoperative and postoperative opioid use and lower recurrence risk [hazard ratio (HR) =0.55, 95% confidence interval (CI): 0.311–0.973; P=0.037] (10). A larger study of invasive breast cancer patients by Cronin-Fenton et al. analyzed opioid impact on recurrence, defined by the Danish Breast Cancer Cooperative Group (DBCG) as locoregional, distal, or contralateral disease. All opioids excluding tramadol, codeine, and dextropropoxyphene were associated with decreased recurrence (adjusted HR =0.75; 95% CI: 0.57–0.99) but a four-fold increase in all-cause mortality (11).

All retrospective studies used multivariate regression models to account for confounding variables. Among the retrospective studies, tramadol correlated with a 0.71-fold decreased recurrence risk, which was attributed to its action on 5-HT receptors and low affinity for mu opioid receptors. Postoperative recurrence was lower in patients receiving nonsteroidal anti-inflammatory drugs (NSAIDs) with tramadol than NSAIDs alone. The investigators concluded tramadol as rescue analgesia may improve oncologic outcomes through proliferation inhibition and promotion of apoptosis (12).

In a retrospective analysis of 1,143 triple-negative breast cancer patients, intraoperative opioid use correlated with greater recurrence-free survival and tumor cell upregulation of tumor-suppressive opioid receptors. Variations in cancer cell genetic profiles are one proposed mechanism (13).

Most studies found no association between opioids and recurrence, although universally low breast cancer recurrence rates limited prospective studies. Three studies utilized paravertebral block (PVB) anesthetic strategies. Cata et al. retrospectively compared PVB versus opioid-based analgesia in non-metastatic mastectomy patients. In this study, recurrence was defined as breast cancer confirmed via biopsy in cases of local, regional, or distant metastasis. PVB reduced opioid use but did not change recurrence-free survival (14). Karmakar et al. randomized MRM patients to general anesthesia with morphine, one-shot PVB without morphine, or continuous PVB without morphine. Five-year local recurrence rates were similar amongst groups (15). Recurrence in this study was defined as local disease. Sessler et al.’s randomized trial 2,132 women to either regional anesthesia with PVB and propofol or general anesthesia with sevoflurane and opioids. Local recurrence rates were similar between groups (adjusted HR =0.97, 95% CI: 0.74–1.28; P=0.84) (16).

Most studies compared recurrence between cohorts receiving varied general anesthesia strategies and opioids. Cho et al. measured recurrence by randomly assigning patients to receive propofol-remifentanil anesthesia with postoperative ketorolac (PRK) or sevoflurane-remifentanil with postoperative fentanyl (SRF). Recurrence in this study was diagnosed via breast and abdominal ultrasound. Insufficient local or distant recurrences limited the analysis (17). Yan et al.’s randomized study compared recurrence-free survival and perioperative opioid use in patients receiving propofol-remifentanil-based TIVA or sevoflurane-based anesthesia. Recurrence in this study was categorized as short-term return of disease. Serum vascular endothelial growth factor C (VEGF-C) and transforming growth factor beta (TGF-β) levels were compared, assessing tumor cell angiogenesis and metastatic potential. TIVA patients required more opioids but had lower postoperative VEGF-C concentrations. The recurrence risk was similar (18). A large retrospective study by Yoo et al. analyzed recurrence-free survival in patients receiving TIVA with propofol-remifentanil versus inhalational anesthesia without opioids and found no difference in recurrence, defined as locoregional or systemic disease confirmed by radiology or histology (19). Lastly, one study analyzed local recurrence with long-term oral opioid receipt. Boudreau et al. retrospectively studied second breast cancer events (SBCE) after curative-intent surgery and categorized patients as either non-chronic or chronic opioid users. They defined recurrence as ipsilateral invasive cancer. Chronic users had more extensive surgery and comorbidities. There was no significant difference in SBCE rates between groups (HR =1.20; 95% CI: 0.85–1.70) (20).

Clinical studies show no association between opioid receipt and distant recurrence

Prospective randomized studies reported neutral or negative associations between perioperative opioids and distant recurrence. Cho et al. found similar disease-free survival rates between patients receiving postoperative ketorolac versus fentanyl (17). Karmakar et al. found no significant difference in distant recurrence between those receiving general anesthesia with intraoperative morphine versus PVB without morphine (15). Cata et al.’s retrospective study of PVB versus opioid-based analgesia in MRM patients found no significant difference in distant recurrence rates (14). Three additional studies also yielded no difference (10,16,19). Conversely, Kim et al.’s work found lower recurrence in patients receiving tramadol versus NSAIDs (12). They defined recurrence as tumor in the ipsilateral breast, regional lymph nodes, and/or chest wall.

Clinical studies of opioids’ impact on overall survival demonstrate mixed results

All studies reporting overall survival were retrospective. Both studies comparing general anesthesia strategies found similar survival rates (10,19). Similar survival outcomes were also reported when comparing PVB vs. opioid analgesia (12). Two studies utilizing oral opioids found contradictory differences in survival. Strongly immunosuppressive opioids correlated with higher all-cause mortality in one study (11). Another found tramadol correlated with a 0.56-fold decreased mortality, and tramadol with NSAIDs was associated with improved survival compared to NSAIDs alone (12). Lastly, varying intraoperative morphine doses did not affect overall survival in Montagna et al.’s retrospective study (HR =0.96 per 10 morphine milligram equivalents increase; 95% CI: 0.89–1.02; P=0.2) (13). Parameters for recurrence were not defined in this study.

Discussion

A review of preclinical works excluded from the present narrative review reveals potential mechanisms for opioids to worsen cancer outcomes. These include altered nitric oxide synthesis, cyclooxygenase (COX)-2 activation, prostaglandin E2 production, signal transduction and activation of transcription 3 (STAT3), mitogen-activated protein kinase/extracellular signal-regulated kinase (MAP-kinase) and Akt signaling pathways (21). Cross-activation of epidermal growth factor receptor and vascular endothelial growth factor receptor 2 (VEGFR2), substance P, and mast cell activation also increase tumor angiogenesis, progression, and distant metastasis (22-29). Farooqui et al. found mice with breast cancer tumors treated with morphine had worse survival compared to mice not treated with morphine but adding a COX-2 inhibitor attenuated this effect (28). Gupta et al. found that opioids stimulated VEGF receptors, nitric oxide and intracellular calcium expression, and vascular proliferation in vitro for human cells and in vivo for rat models. While the opioid receptor antagonist naloxone could not reverse these effects (25), other studies show naloxone alone is sufficient to inhibit morphine-induced tumor progression, suggesting an opioid receptor-mediated mechanism (24).

Studying the association between opioids and recurrence in higher-risk cancers could show a larger effect size. Most patients in Karmakar et al.’s randomized trial had early-stage and estrogen receptor-positive cancers, which have lower metastasis or recurrence risk than advanced-stage or triple-negative cancers (15). Opioid users in the Cronin-Fenton study had more early-stage disease and comorbidities than nonusers. This may have been attributed to lower recurrence but higher mortality. These opioid users also had greater concurrent NSAID use (11,30). A retrospective study found patients receiving intravenous ketorolac before incision had a lower recurrence risk (31). This benefit was greater in overweight patients, making it a promising adjunct for overweight patients meriting further research (32).

Different mechanisms across opioid classes may also contribute to mixed results. Tramadol stimulates serotonergic and noradrenergic nociceptors with opioid receptors, inhibiting proliferation and inducing apoptosis in human breast adenocarcinoma cells through 5-hydroxytryptamine (HT)2B receptors (21). This contextualizes the lower recurrence in the tramadol cohort in Kim et al.’s study. An animal-model immunoassay ascribed tramadol’s immunostimulant properties to its serotonergic properties, not its mu receptor effects. The immune effects of tramadol, despite its classification among opioids, is a relevant subject for future research.

Strengths and limitations

The present review found contradictions in available clinical and preclinical study findings, consistent with that by Lucia et al. (14,33,34). Our review builds upon the previous literature by stratifying studies between local and distant recurrence. Mixed results in the rates of local recurrence suggest a need for a more in-depth review of patients with higher risk of recurrence. Study design and low recurrence in contemporary breast cancer populations limit the existing literature (35). Four studies found lower recurrence in cohorts receiving more opioids but were limited by bias inherent to retrospective study design (10-13). Comparison groups were often unequal in the retrospective studies. Variations in opioid dose, type, and other factors influencing cancer outcomes, including patient characteristics, cancer staging, and adjuvant therapy were difficult to assess.

Different mechanisms across opioid classes may also contribute to mixed results. Tramadol stimulates serotonergic and noradrenergic nociceptors with opioid receptors, inhibiting proliferation and inducing apoptosis in human breast adenocarcinoma cells through 5-hydroxytryptamine (HT)2B receptors. This contextualizes the lower recurrence in the tramadol cohort in Kim et al.’s study. An animal-model immunoassay ascribed tramadol’s immunostimulant properties to its serotonergic properties, not its mu receptor effects. The immune effects of tramadol, despite its classification among opioids, is a relevant subject for future research.

Since the inception of this review, several trials studying the effects of opioids on cancer recurrence are underway. While outside the scope of the present review, these studies analyze incorporate additional patient and tumor covariates that may influence the association between opioids and breast cancer recurrence and include mu-opioid receptor polymorphisms, other genetic biomarkers (36,37), immunological processes (38). and hormone receptor-specific responses to opioids (39).

Despite the mixed results in this review, limiting superfluous opioid prescribing can change the opioid epidemic surge seen during the COVID-19 pandemic (40). Surgeons prescribe approximately 70% of opioids in the US, and one in five mastectomy patients use opioids one year after surgery (5,41). Multimodal analgesia protocols, including local anesthetics, regional blocks, and NSAIDs, can effectively decrease perioperative pain and limit prescription opioid diversion (42-47). Ongoing clinical trials in the US, Austria, China, Sweden, Canada, Spain, and South Korea are investigating the feasibility and sequelae of breast cancer surgery with minimal to no utilization of opioid anesthesia and analgesia (48).

Conclusions

Future work investigating the association between opioids and cancer outcomes should be prospective in nature with balanced comparison groups, limited to one non-immunosuppressive opioid type, with long-term follow-up. Focusing on high-risk patients with greater risk of recurrence, such as those with node-positive triple-negative breast cancer, could be considered. To our knowledge, this review is the first to summarize clinical studies examining the association between opioids and breast cancer outcomes stratified by local and distant recurrence. Despite the mixed results of the available clinical data, most of which is retrospective in nature, some preclinical works have described potential mechanisms for adverse oncologic outcomes with the receipt of opioids. These should provide further impetus to continue to investigate opioid-sparing pain management options for patients undergoing surgery for breast cancer.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tbcr.amegroups.org/article/view/10.21037/tbcr-23-6/rc

Peer Review File: Available at https://tbcr.amegroups.org/article/view/10.21037/tbcr-23-6/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tbcr.amegroups.org/article/view/10.21037/tbcr-23-6/coif). KER has received research funding from the Robert A. Winn Diversity in Clinical Trials Award Program and speaker’s honoraria from Pacira Pharmaceuticals, and she also received support of consulting fees from Roche Diagnostic Solutions, Merck, physician consulting advisory board and Virtual tumor board platform. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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