Pain is defined by the International Association for the Study of Pain (IASP) as an “unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage” [1], demonstrating that pain is a complex biopsychosocial symptom. Cancer-related pain (CRP) affects more than 65% of patients with advanced cancer [2] and is one of the most common [3] and highest priority symptoms for these patients ^[4][5][4,5]. CRP impacts multiple aspects of wellbeing, including physical, emotional, and interpersonal domains, and improper management can thereby have negative impacts, such as sleep disturbance, depression, distress, and diminished quality of life (QoL) [6]. Manifestations of pain are not only physical, but are inextricably linked to patient perceptions, which are modulated by mood, culture, psychological wellbeing, and personal beliefs ^[7][8][7,8]. Due to the complex nature of CRP, the provision of appropriate pain management is a difficult task, but is essential for maintaining QoL for a majority of patients with advanced cancer [9].

The population of patients with advanced cancer is largely understudied [7], and these patients have unique needs as a result of facing incurable prognoses and living with cancer as a chronic disease. Over recent years, more advanced treatment options have allowed patients with terminal diagnoses to have significantly increased survival times [7]. For example, among young women with metastatic breast cancer, 5-year survival rates increased from 45.6% to 56.5% from 2005–2009 to 2010–2015, while survival rates remained relatively stable among women with non-metastatic disease over the same period [10]. In many cases, patients with advanced stage disease are now living with cancer and its effects for many years [11] and may experience prolonged existential burden, psychosocial distress, and physical symptoms as a result. Patients with advanced cancer commonly report high levels of depression, anxiety, and hopelessness [12], in addition to physical symptoms including pain, nausea, fatigue, and dyspnea [13].

The goal of treatment for these patients is generally palliative, focused on the alleviation of symptoms, rather than curative-intent. In these cases, the healthcare system’s primary role is centered on providing symptom control and maintaining patient QoL throughout the disease trajectory. Due to a high prevalence of pain, coupled with increasing survival times and differing treatment priorities, barriers to effective symptom management are particularly impactful for patients with advanced cancer [14].

2. The Role of Opioids in Cancer Pain

Opioids are considered to be a gold-standard therapy for cancer pain management, and the World Health Organization (WHO) recommends them as the first choice for the treatment of moderate-to-severe CRP [15]. Opioids act as analgesics by binding receptors on the nociceptive pathway and thereby reduce perception of pain at the somatosensory cortex [16]. Common opioid therapies used in the treatment of CRP include morphine, hydromorphone, oxycodone, codeine, and fentanyl. Opioid analgesics have been shown to be highly effective ^[17][18][17,18], and are designated as essential medicines for palliative care [19]. Clinically meaningful alleviation of CRP can be achieved through opioid use in approximately 80% cases [20], and while multimodal management strategies are needed for the remaining approximately 20% of cases [21], opioid therapies are an indispensable resource for pain and symptom management among patients with cancer. Guidelines for the treatment of cancer-related pain recommend that opioids be prescribed to patients with moderate-to-severe pain, unless contraindicated, and should be prescribed at the lowest dose necessary to achieve adequate analgesia [22].

3. The Opioid Epidemic and Changes in Opioid Prescribing

North America is facing an ongoing opioid epidemic which poses one of the most challenging and pressing public health issues of our time ^[23][26]. The Government of Canada has reported more than 30,000 opioid toxicity deaths from 2016 to 2021, and a worsening of the overdose crisis over time ^[24][27]. In recent years, numerous updated guidelines have been published with the intent of curbing the prescribing of opioids in response to high levels of non-medical opioid use (NMOU) and associated adverse effects ^[25][26][28,29]. However, it is important to note that these guidelines were not intended to impact patients experiencing CRP and were specifically established for the treatment of non-cancer pain ^[27][30]. Despite the intended limited scope of updated guidelines, declines in opioid prescribing have been observed among oncologists in recent years ^{[28][29][30][31]}[31,32,33,34], and these declines have been particularly pronounced among patients with metastatic cancers. From 2011 to 2017, opioid prescriptions for patients with bone metastasis were found to decline significantly, in terms of both proportion of patients receiving prescriptions as well as dosage level ^[30][33]. It is difficult to determine if these changes represent an appropriate correction in over-prescribing by certain practitioners, greater reliance on alternative methods of pain management, or could represent a concerning exacerbation of issues of pain undertreatment ^[32][35].

4. What Are the Risks of Opioid Use among Advanced Cancer Patients?

There is a variety of evidence indicating that there are significant differences between cancer and non-cancer populations in terms of the risks of opioid use. The lifetime prevalence of opioid-use disorder among non-cancer patients prescribed long-term opioid therapy has been estimated at 41.3% ^[33][37], compared to an estimated prevalence of 8% among patients with cancer-related chronic pain ^[34][38]. In terms of overdose deaths, there were 8.97 opioid deaths per 100,000 people among the general population in 2016, compared to 0.66 opioid deaths per 100,000 among cancer patients ^[35][39]. Given the differences between these populations, it is clear that prescribing practices or guidelines should not be extrapolated from the general population to patients with cancer. While there are differences between cancer and non-cancer populations, consideration of the risks related to opioid use is still relevant when prescribing opioids to cancer populations. The older literature suggests that NMOU among patients with cancer is low compared to the general population ^[36][37][40,41]. However, while commonly cited, these studies are outdated and may no longer be relevant in the opioid epidemic era. A more recent review indicated that approximately 20% of patients with cancer are at high risk for opioid use disorder ^[38][42]. Similarly, a recent study of 1554 patients taking opioids for cancer pain found that 19% developed NMOU behaviors ^[39][43]. When specifically investigating patients with advanced cancers, a study found that 18% were diagnosed with chemical coping ^[40][44]. While there are a variety of metrics for evaluating NMOU which are difficult to compare, it is increasingly evident these issues are applicable to the cancer community, including those with advanced cancer. Chronic opioid use, which may be a risk factor for NMOU ^[41][45], has been defined as use of medically prescribed opioids for at least 90 days ^[42][46]; this outcome has not commonly been considered a concern for patients with advanced cancer given their historically short survival times. The significant increase in survival times among this population means that consideration of chronic use has become applicable, and studies on this topic are timely, if not overdue ^[32][43][35,47]. Among opioid-naïve patients after curative-intent surgery for cancer, the risk of new persistent opioid use has been estimated at approximately 10.4% ^[44][48]. There are no population-based estimates for the risk of chronic opioid use in patients with advanced cancer. The inability to provide patients with this information may lead to exaggerated fears regarding long-term opioid use, and the exclusion of these patients from studies may be damaging, rather than shielding, in terms of patient perceptions. Further concerns for patients receiving opioid therapy include adverse effects such as the development of tolerance, physical dependence, cognitive dysfunction, constipation, and nausea ^[45][49]. While there are guidelines relating to the management of opioid-induced adverse effects among patients with cancer ^[46][47][48][50,51,52], there is limited information on the incidence or prevalence of effects related to dependence and tolerance. The onset of adverse effects, as well as their potential for alleviation, are important considerations for patients, who need to weigh the tradeoffs between these symptoms, their impact on wellbeing and functioning, and the potential for experiencing freedom from pain.

5. Defining Opioid Stigma

Stigma has been extensively studied and theorized following the publication of Goffman’s seminal text ^[49][68], which defined stigma as “possessing and attribute which makes (someone) different from others” and “of a less desirable kind”. Since then, a variety of academic and colloquial meanings have been attached to the concept. The stigma is existing when (1) “people distinguish and label human differences”, (2) “dominant cultural beliefs link labeled persons to undesirable characteristics”, and (3) “labelled persons are placed in distinct categories so as to accomplish some degree of separation of ‘us’ from ‘them’ ^[50][69]. Extensive literature has demonstrated that stigma follows social structures including race, socioeconomic status, and gender, and can contribute to inequities in health ^[51][70]. In healthcare settings, stigmatization can negatively impact patients’ self-perception, social support, and willingness to seek services, and these effects may be heightened by further stigmatizing behavior of healthcare professionals ^[52][71]. Stigma may be categorized as either public stigma or self-stigma, and it has been shown the development of self-stigma follows the establishment of public stigma ^[53][54][72,73]. In relation to opioids, it has been argued that the stigmatized history of opioids has defined the current epidemic, rather than arising as a parallel process in response to the crisis ^[55][74]. Regardless of the nature of the causal relationship between the modern opioid crisis and opioid stigma, it is clear that both medical and non-medical opioid use are affected by dimensions of stigma in public, clinical, and internalized domains ^[56][75]. Opioid stigma may be experienced from external sources, including media, peers, or healthcare providers, as well as internally, relating to patients’ own feelings of fear or shame.

6. Public Stigma and Opioid Use

Over the past 20 years, news media coverage on the opioid epidemic and prescription opioids has dramatically increased, with more than 35,000 online news reports from 2018 to 2019 in the United States alone ^[57][76]. News stories discussing the opioid epidemic have been found to be far more likely to include stigmatizing terms, such as addict, compared to less stigmatizing alternatives, such as substance use disorder ^[58][77]. Public attitudes towards individuals with opioid use disorders have been found to have high levels of stigma, even among individuals with personal experiences relevant to opioid use ^[59][78]. The highly publicized and stigmatized presentation of the opioid crisis has resulted in high levels of stigma within the public consciousness, and these perceptions have permeated the oncology setting ^[56][75], creating an environment which encourages of the formation of self-stigma among patients with cancer.

7. Discussion: Opioid Stigma in Cancer Settings

7.1. Pharmacovigilance & Indications of Opioid Stigma among Healthcare Professionals

The WHO identifies pharmacovigilance as aiming “to enhance patient care and patient safety in relation to the use of medicines, and to support public health programs by providing reliable, balanced information for the effective assessment of the risk-benefit profile of medicines” ^[60][79]. This concept is essential for safe and effective prescribing practices, including the prescribing of opioids for cancer pain management. However, disproportionate focus on the risks related to certain pharmaceuticals can lead to misuse of a benefit-to-harm framework, and thereby cause reluctance to enact optimal prescribing practices. The wide-reaching nature of the opioid epidemic may mean that both prescribers and patients are more likely to have personal experiences with opioid misuse or addiction, in addition to extensive press coverage, which may impact ideas about the utility of and risks associated with opioid use. Healthcare professionals often have very differing views on the role of opioids in cancer pain management, which may be related to their discipline and the type of care they provide ^[61][80]. For example, palliative care physicians may have very different perceptions of the dosage level and duration of prescription that is appropriate for patients, when compared to surgeons who typically prescribe opioids for acute post-operative pain ^[61][62][80,81]. While the adverse effects of the opioid epidemic are most prevalent in North America ^[63][88], manifestations of opioid stigma have been observed globally. Among physicians managing cancer pain across 10 Asian countries, excessive regulation and patient fears of addiction were identified as key barriers to opioid prescribing and pain management ^[64][89]. In a survey of physicians in Cyprus, 70% of respondents identified opiophobia as a barrier to the appropriate management of cancer-related pain ^[65][90]. Strict regulation on opioid use was identified as a barrier in Palestine and Qatar ^[66][67][91,92], and, similarly, across Europe excessive regulatory barriers in the accessibility of opioids have been identified ^[68][93], which may negatively impact the management of cancer pain. Dimensions of opioid stigma expressed by healthcare professionals are further affected by patient demographics, which may result in differential pain management that is prejudiced against minority or disadvantaged groups. Studies suggest that healthcare providers’ distinction between patients who have legitimate or illegitimate pain tends to be influenced by class and racial characteristics ^[69][70][94,95], similar to the delineation of stigma within these groups. Qualitative accounts have also demonstrated that healthcare providers are perceived to have personal biases related to the risks and benefits of long-term opioid therapy that are shaped by personal experiences and patient characteristics, including race and housing status ^[61][80]. Race and insurance type have both been found to be independently associated with the type of opioid prescribed to cancer outpatients ^[71][96], and there is strong evidence of racial disparities in pain burden and management in cancer settings ^[72][97]. Stigma is inextricably related to these health disparities, as minorities and economically disadvantaged groups are easily stereotyped and assigned undesirable characteristics that are distanced from the “us” group.

7.2. Self-Stigma: Patients’ Experience with Internalized Stigma and Opioid Use

Poor opioid adherence has been reported among patients with cancer, and research has found consistent underutilization of opioids by patients with cancer pain ^[73][74][105,106]. A study comparing longitudinal barriers to cancer pain management found that 40% of patients reported inadequate use of analgesics, and this high rate of inadequate management has been a consistent issue for the past 20 years ^[75][107]. The study additionally found that patient concerns about the risks of opioids have increased over this period. In a study of Taiwanese patients with cancer, negative beliefs regarding opioids were found to be significantly associated with poor analgesic adherence ^[76][108]. Stigma is one of the most significant patient-identified barriers to adequately managing pain, manifesting as internalized feelings of fear, shame, and discrimination based on their use of opioid analgesics ^[75][77][100,107]. Fear is one of the most commonly reported feelings relating to opioid use among patients with advanced cancer, and may arise from concerns regarding addiction, dependence, diminishing opioid efficacy, and side effects ^{[77][78][79][80][81][82][83]}[100,102,104,109,110,111,112]. Concerns of addiction were found to be among the greatest patient-perceived barriers to cancer pain management in a review of both Western and Asian cancer patients ^[84][113]. The opioid epidemic has been identified as foundational to patients’ beliefs regarding the use of opioids, and media or news coverage are contributors to patient fears ^[78][102]. Patients commonly view opioid use as an ethical issue and see taking pain medication as “caving in” ^[78][102].  Beyond fears regarding the risk of opioid use, patients often feel shame or guilt, which are constructs of the stigma surrounding opioid use. While it may be viewed as rational that patients have concerns about opioid dependency or side effects, feelings of shame and guilt, especially among patients who are following medical instruction and gaining clinical benefit from opioids, are largely detrimental. Even when partaking in opioid-restricting behaviors, patients express feeling morally compromised and experiencing guilt relating to substance use ^[78][102]. It was common for patients to draw false equivalencies to other behaviors, such as smoking, drinking, or other drugs ^[78][82][102,111], and these comparisons contribute to increasing feelings of shame.

8. Conclusions

Opioids are an essential therapeutic option for symptom and pain management among patients with advanced cancer. However, the opioid crisis has led to highly publicized and widespread stigmatization of opioid use, which affects both patients and providers. While responses to the opioid crisis were not intended to affect the cancer population, stigma has transcended the intended scope of guidelines and become a significant barrier to pain management for patients with advanced cancer. Stigmatization manifests among healthcare professionals who provide access to opioids, and can result in disparities in access to resources among minorities or groups with increased stigma. In spite of healthcare professionals being the gatekeepers of opioid analgesics, the most significant barriers to cancer pain management relate to the self-stigma experienced by patients. Patients with advanced cancer have fears related to addiction and diminishing returns, shame regarding their need for opioids, and difficulties communicating with providers about these topics. Self-stigma can act as a barrier to pain reporting, which makes physicians’ pain assessment impossible. This stigma may also act as a barrier to prescription adherence, which means that, even in the case of perfect prescribing practices, patients may not experience freedom from their pain.