This project stems from a multidisciplinary team approach to better understand the consequences of drug interactions known to occur commonly in the management and care of patients with cancer. In contrast with typical scoping review methodology comprised exclusively of clinical data, this study incorporates a more comprehensive mapping of the literature, inclusive of preclinical data. In many clinical studies, it is difficult or impossible to disambiguate patient outcomes related to opioid use from the consequence of pain or pain management. This is because opioid use is often the measure by which pain is assessed. Therefore, our approach will enable a new perspective on an old and controversial problem.

Opioid analgesics are among the most frequently administered drugs for patients with cancer, and their use often coincides with active chemotherapeutic regimens [1]. The intended target for opioid analgesics is the µ-opioid receptor (µOR) expressed within the central nervous system [2]. However, the µOR is also present in diverse cancer types [3]. In cancer cells, µOR activity can stimulate intracellular signal cascades that regulate processes of cell survival and death and can coincide with the same signal cascades triggered by cytotoxic chemotherapy [3-12]. Some clinical studies for specific cancer types have identified the µOR as a negative prognostic factor and associated with chemotherapy resistance [3,13-23].

Paradoxically, opioids have demonstrated potential to both augment and inhibit cancer cell growth and survival as well as chemotherapeutic activity. For some types of cancers, opioid use is linked to metastasis, proproliferative effects, and decreased patient survival, while in other cancer types, opioids are associated with improved cancer cell killing and improved patient outcomes [16-19,21-47]. At present, there is no consensus on the risk or benefit posed by opioids in the context of malignancy and its treatment.

While multiple clinical studies have been conducted to evaluate the relationship between malignancy and its treatment with the µOR and analgesic opioid use, interpreting the risks or benefits of opioid use on tumor growth remains challenging and often confusing. Public response to some literature reports has led to surges in demand for opioids as potential antineoplastics. In contrast, other published data have led to concern that opioids will be withheld in the presence of suffering for fear of promoting malignancy [11,48,49]. Therefore, an improved understanding of the effects routinely prescribed opioids can have on any neoplasm, cancerous lesion, or malignancy and its treatment is an urgent public health need. A scoping review approach can help meet this need by organizing the existing clinical and preclinical evidence in a manner suitable to better distinguish clinically meaningful patterns and identify key knowledge gaps.

By examining both clinical and preclinical evidence together, 3 major challenges found in interpreting the clinical literature can begin to be addressed. First, clinical studies typically have a small n and focus on a specific cancer subtype, and among these, they differ in experimental design, intervention (eg, type, timing, and route of opioid administration), and patient population. Second, clinical opioid concentration data are lacking. Opioid concentration data are critical to establish the consequences of opioid use in the context of malignancy. As opioids are characterized by high inter- and intraindividual pharmacokinetic (PK) variability, the common practice of using opioid dose as a surrogate is a highly flawed means of estimating tumor tissue concentrations [50,51]. Finally, clinical studies seeking to assess the risks and benefits of opioids related to disease progression are frequently confounded by the role of pain and pain management on patient outcomes [41,52]. Preclinical studies have the potential to fill gaps in knowledge regarding opioid effects for certain cancer models at known concentrations and are not influenced by pain.

It is to be expected that the relationship between heterogeneous forms of cancer, µOR expression, and the clinical use of various analgesic opioids (routes of administration, formulations, and patterns of use) will be complex. Nonetheless, a scoping study approach can map evidence from both clinical and preclinical studies that will augment one another in the detection of meaningful associations between analgesic opioid exposure and the potential risks or benefits to patients with cancer.

Our objective is to map preclinical and clinical study data on therapeutically relevant concentrations of opioids effects on tumor growth or survival, or alteration on the antineoplastic activity of chemotherapeutics. We will map and evaluate published evidence regarding (1) opioid concentration data from human subjects with cancer, yielding a “physiologic range” to better interpret available preclinical data, (2) patterns of opioid exposure and disease and treatment-related patient outcomes, and (3) the influence of opioids and µOR activity on cancer cell survival and growth, as well as changes in susceptibility to clinically used chemotherapeutics. Apparent contradictions and clinically relevant knowledge gaps concerning the risks or benefits of analgesic opioid use in the context of malignancy can be better understood and clarified by using a systematic approach to catalog and examine existing literature from a pharmacologic perspective.

A search for existing evidence reviews or protocols on topic has been conducted (TC) in PROSPERO and MEDLINE (Ovid) on February 6, 2021. None were identified by the team as being on topic.

Prior to developing the scoping methodology protocol, a pilot study was undertaken to evaluate existing clinical and preclinical data concerning the effects of analgesic opioids on malignancy and its treatment (JEC). The central research question proposed for this study has been sought before and remains the source of much controversy. However, as the pilot study demonstrated, harnessing both clinical and preclinical information can bring into focus central concepts, such as the use of physiologic versus supraphysiologic opioid concentrations and biologic context. These concepts are often absent in the broader discussion of opioids and malignancy yet essential to solving some of the seeming contradictions. As this prestudy data, using an inclusive approach, revealed novel and informative patterns, we anticipate, a full scoping review will provide a new framework to view existing evidence and therefore, its interpretation.

The pilot study used MEDLINE (Ovid) for years 1946-2021, titles and abstracts were screened for inclusion (full publication). References of included studies were additionally assessed for relevancy and potential inclusion. Study data were collected and managed using Excel (Microsoft Corp) and GraphPad Prism (version 9; GraphPad Software, Inc). Data elements extracted were manuscript information (journal, title, authors, and year), study type (clinical [human subjects], including ex vivo), preclinical (in vivo [animal model] or in vitro), malignancy (type, subtype, model, or cell line), ligand (µOR agonist [ie, most analgesic opioids], antagonist, and partial agonist) and concentration information (eg, IC₅₀), any coinciding antineoplastic treatment, and predominant effect reported (ie, promotion or inhibition of tumor growth or chemotherapeutic activity). For ex vivo or in vitro data, “clinical” concentrations of µOR agonists were based on human subject studies reporting maximal peak concentrations experienced by adult patients with cancer receiving opioids as part of the standard of care: morphine (≤350 nM), fentanyl (≤10.8 nM), methadone (≤3.2 µM), and oxycodone (≤320 nM), and antagonists: nalmefene, methylnaltrexone, naltrexone, and naloxone (≤1 µM).

Data were extracted from 94 studies found to meet the pilot study criteria. From each study, findings were categorized as “tumor growth,” “tumor death,” or “no effect.” A given study could report multiple findings, for instance, morphine (µOR agonist) could be found to stimulate cancer cell proliferation in a breast cancer cell line, while naloxone (a µOR antagonist) may be found to induce cancer cell apoptosis. Aggregated findings of opioid-associated effects on cancers are presented in Figure 1 [7-10,12,17-23,30,31,33-40,42,46,52-121].

The following conclusions have been drawn:

The results of this scoping review will be presented using a descriptive narrative form as well as graphical and tabular representations. The results will be structured, as appropriate, to emphasize the effects of prescription opioids by cancer classification as well as chemotherapy type. Additionally, study results concerning data classified as preclinical, translational, and clinical will be presented distinctly to facilitate comparison. The protocol for the scoping review was initiated in February 2021 at the University of Utah and is expected to be completed in August 2023. The results of the scoping review will be disseminated through regional and national scientific conference proceedings and presentations, stakeholder meetings, and by publication in a peer-reviewed journal.

This scoping review will map diverse studies spanning from preclinical to clinical regarding the intersection of opioids with malignancy and its treatment. The interpretation of opioid-malignancy interactions within a clinical context is often confounded by pain and its management. It is therefore both novel and necessary to include preclinical study data to identify key knowledge gaps, begin to reconcile seeming conflicting data (eg, opioids foment cancer growth vs opioids kill cancer cells) by setting a context to parse the biologic and molecular complexities of opioid impact on malignancy and its treatment, and ultimately, inform patient treatment algorithms to optimize outcomes. The knowledge presented in the scoping review will help to inform and improve the design of studies to assess the unmet medical need to understand the risks and benefits associated with opioids extending to the potential to impact cancer and its care.

This scoping review study has several strengths. First, our scoping review approach will be inclusive of studies spanning the spectrum of published data available from clinical to in vitro. Popular opinion and clinical judgment regarding the potential for opioids to affect malignancy have been deeply influenced by the publication of basic (in vitro or ex vivo) studies. Therefore, expanding this review to include both clinical and preclinical studies provides a new perspective on the topic, acknowledges that basic studies impact clinical care and shape patients’ attitudes, and addresses limitations specific to the opioid-malignancy question in the context of clinical studies. Current clinical studies examining the opioid-malignancy question, often retrospective, are confounded by pain and the management of pain. Adequate pain management is associated with improved patient survival; therefore, interpretation of the potential effects of opioid use on the malignancy itself is challenging to interpret. Finally, despite the intense attention the topic has received, the key dimension of opioid concentration is often not addressed. Therefore, incorporating data from clinical and preclinical studies into this review with an emphasis on systemic opioid exposures (concentration) is warranted, and based on the preliminary data collected, aids in clarifying seemingly contradictory findings pointed to in existing reviews.

This scoping review also has limitations. Specifically, no quality assessment of the included studies will be performed. Relevant data may be missed, as we are searching for published studies only. We selected several sources and developed sensitive search strategies to increase the discovery of eligible studies.

The topic of opioid impact on cancer and its treatment is not new but remains controversial and clinically relevant. This scoping review seeks to encompass preclinical and clinical studies to generate a comprehensive landscape for interpreting the existing literature within pathophysiologic and pharmacologic contexts. We hope this study will be used to identify key knowledge gaps and advance future studies aimed at improving patient outcomes.