Despite the recent evolution of guidelines that address safety associated with therapeutic use of opioids, guidance in the care of patients experiencing cancer-associated pain is commonly limited if not expressly excluded.1 , 2 The United States is suffering from a historic epidemic of prescription drug abuse.3–5 Patients with cancer frequently experience pain6–10 and are frequently treated with opioid medications.8 , 10 , 11 Often opioids are the primary or exclusive analgesic utilized to treat cancer-associated pain during treatment or at the end of life. Yet, there is minimal contemporary guidance on balancing efficacy and safety in these populations.6–9 , 11–13
The opioid epidemic has raised awareness of excessive prescribing and overreliance on opioid therapy for the treatment of chronic pain, as well as the dubious distinction attributed to the United States as disproportionately the largest consumer of opioids in the world.14–17 In the last decade, there has been no shortage of opinions, position statements, or guidelines related to opioid therapy for noncancer-related pain. The medical literature is replete with data that demonstrate evolving perspectives from before and after the recognition of the opioid abuse epidemic. Much of this information was collected from patients in the noncancer pain population. We have since learned that opioid therapy was misconstrued as safe and that it requires a sophisticated risk/benefit analyses to guide initiation, continuation, and discontinuation throughout treatment.
THE CLINICAL CHALLENGE OF CANCER AND PAIN
A 65-year-old woman with metastatic pancreatic cancer and severe cancer-associated pain is referred to your pain clinic for optimization of her pain medication regimen. Accompanied by her husband, the patient reports severe back and abdominal pain that significantly limits her function, ability to sleep, and quality of life. The patient’s current medication regimen includes fentanyl transdermal patch 100 µg/h every 72 hours, oxycodone SR 40 mg twice daily, and 6 oxycodone 15 mg tablets per day. Her total 24-hour oral morphine equivalents are estimated to be 570 mg/d. On evaluation in clinic, the patient and her husband report that her pain is not well controlled on the current regimen and request an increase in her opioid dosing. Upon review of her medical records, including the state prescription drug-monitoring program, the patient had recently been issued oxycodone SR and oxycodone prescriptions multiple times in the same month from multiple other providers outside of your health care system. When you raise questions in regard to these findings, the patient’s husband angrily reports that it is because his wife’s pain is inadequately controlled and that you need to do something about that.
This clinical scenario is not uncommon and raises important questions about the expectations for managing patients experiencing cancer-associated pain. The current epidemic of prescription drug abuse in the United States has engendered specific recommendations for improving safety in opioid prescribing through federal, state, and professional prescribing guidelines.1 , 2 However, these guidelines largely exclude patients with cancer and terminal illness, leaving gaps in guidance for cases like the one described above, where aberrancy may be self-evident or detected through vigilant practice. Such limited consensus guidance leaves many questions for prescribers charged with addressing suffering and safety in patients with terminal illness. Should evidence of aberrant behavior be grounds for tapering completely off of opioids in patients with terminal cancer and severe cancer-associated pain? Are random urine drug screens indicated in this patient population? Are there medication options other than full μ-opioid agonists that may be as efficacious and carry less risk? These are just some of the many difficult questions that may arise.
BACKGROUND ON OPIOID ABUSE IN THE UNITED STATES
Physicians are charged with dual responsibilities to do no harm as well as to respond to human suffering. Opioid medications are essential drugs for treating pain, widely used, and efficacious for certain types of pain. Unfortunately, these medications are also potentially harmful to the patient and the surrounding community. This problem is further compounded by inadequate education about the assessment, evaluation, and treatment of pain, in addition to limited research and clinical resources.18
Despite the growing awareness of excessive opioid prescribing for chronic pain, unintended overdose deaths related to prescription opioids have continued to increase in the United States.1 , 5 Opioid drugs were involved in more than 12,700 deaths in the year 2015, reflecting an increase of 2.6% from the prior year.1 , 5 Irrespective of data that suggest prescription opioid abuse is not slowing down, opioid prescriptions have decreased in the United States. Since 2012 to May 2016, all opioid prescriptions have decreased 12%–18%.19 Sadly, this reduction has not translated into decreased deaths associated with opioid use, in part related to mortality from heroin and synthetic illicit fentanyl.20–22 Thus, opioid-related deaths in the United States appear to be driven by prescription opioid pain medications, as well as by illicit opioids (predominantly illicit fentanyl and heroin).
Worldwide attention to prescription drug abuse and overreliance on opioids has driven notable regulations and professional treatment guidelines. In 2016, the Centers for Disease Control and Prevention (CDC) in the Unites States released its guideline for prescribing opioids for noncancer pain. Although it addresses chronic pain in cancer survivors, this guideline does not address the management of pain in active cancer patients during treatment or at the end of life.1 Other major opioid prescribing guidelines that postdate the recognition of the epidemic of prescription drug abuse also have limited or no guidance for addressing misuse, abuse, or addiction in cancer or terminal illness.2 , 13 , 19 A full discussion of the epidemic of prescription opioid misuse and abuse is beyond the scope of this review and can be found elsewhere in this supplement, as well as many other publications.23
OPIOID MISUSE, ABUSE, AND ADDICTION IN PATIENTS WITH CANCER OR TERMINAL ILLNESS
Many published articles and guidelines that provide support and guidance for prescribing opioids for cancer-associated pain were published before widespread recognition of the prescription opioid epidemic. Furthermore, few if any addressed safety concerns and harm reduction.6–9 , 12 , 13 The World Health Organization (WHO) originally developed the WHO analgesic ladder for cancer pain in 1986 in response to the internationally identified problem of inadequate treatment of cancer-associated pain. The WHO guideline was subsequently updated in 1996, well before recognition of the US epidemic of prescription drug abuse. Recommendations were essentially to start with nonopioid medications and escalate and combine opioid with nonopioid therapy in a stepwise fashion based on the severity of the pain.12 The European Association for Palliative Care (EAPC) guidelines were published in 2012 subsequent to recognition of the prescription opioid epidemic. The EAPC provided 16 evidence-based recommendations for treating patients with cancer-associated pain. The recommendations cover pertinent topics including but not limited to the role of specific opioids, opioid switching, alternative routes of opioid administration, management of common opioid side effects, and the role of adjuvant medications.8 The EAPC recommendations offer guidance in regard to how to initially approach treatment of cancer-associated pain and considerations for refractory symptoms. However, neither the WHO guidelines nor the EAPC recommendations address the major safety concerns that face contemporary prescribers, particularly in patients who have cancer or terminal illness concurrent with a history or evidence of prior drug misuse or abuse.
The 2013 National Comprehensive Cancer Network guidelines on management of cancer pain began to address safety issues. Recommendations are made to monitor for risk factors of misuse and abuse including utilization of standardized tools such as the SOAPP-R (Screener and Opioid Assessment for Patients with Pain-Revised) or ORT (Opioid Risk Tool), and COMM (Current Opioid Misuse Measure),24–27 as well as utilization of substance abuse consultation if concern exists. However, the exact details in regard to what diagnostic tests (such as urine drug screen) to employ and how often to use them are not specifically addressed. Furthermore, there are no recommendations in regard to if and when to cease opioid therapy or consider buprenorphine.9
Aberrant behaviors are an important component of prescription drug abuse, but may not be equivalent in severity or cause for alarm.28 , 29 The definition of aberrant behavior varies across experts and groups.30 , 31 Gourlay and Heit32 offer a useful operational definition of aberrant behavior: “a behavior outside the boundaries of the agreed-on treatment plan, which is established as early as possible in the doctor-patient relationship.” Aberrant behavior can manifest in a multitude of forms, including requests for early refills, unauthorized dose escalation, the borrowing or stealing of medication from others, aggressive complaining, and diversion.33–35 Aberrant behavior in patients with cancer-associated pain is not uncommon.36 , 37 Recently, a study evaluated 432 patients with cancer-associated pain who were treated with opioid therapy by palliative medicine specialists.37 These authors reported that 18% of patients were using opioids in a nonprescribed manner to cope with the various stressful events associated with the diagnosis and management of cancer.37
In light of the growing concern for persistent significant opioid misuse and abuse in both chronic noncancer pain patients and cancer pain patients, Carmichael et al36 undertook a review of the current literature from 1995 to 2016, specifically focusing on the risk of opioid abuse in patients with cancer. A total of 34 published reports were reviewed, from which it was determined that at least 1 in 5 patients with cancer are at increased risk for opioid use disorder. This work also found a strong association between patients identified as being at increased risk and concerning outcomes including aberrant behavior, prolonged opioid use, elevated oral morphine equivalent doses, higher rates of health care utilization, and symptom burden.36
To date, only a handful of studies have assessed the level of infrastructure in place to identify, evaluate, and manage opioid misuse, abuse, and addiction in cancer patients with pain. In 2013, Blackhall et al38 reported that less than half of hospice agencies require mandatory substance abuse training, only 43.5% had policies regarding screening for substance abuse in patients, and 21.7% had policies in place for screening for diversion. Critically, there was also a lack of policy regarding how to approach opioid management once abuse or diversion was identified. It was concluded that hospice facilities appear to lack mandatory training and policies for substance abuse and diversion in patients experiencing cancer. Most recently, Sacco et al39 reported on a regimented analysis of substance use assessment in a random sample of US Medicare-certified hospice programs. Of the 105 distinct hospice agencies included in the study, 68% of the agencies were found to include some form of assessment of substance use or related problems; however, the assessments were determined to be relatively cursory. None of the assessments utilized were standardized instruments, and none of the assessments directly evaluated the potential diversion of pain medications. The authors concluded, hospice care agencies need to implement validated structured assessment instruments to assist in screening.39 Tan et al40 surveyed Accreditation Council for Graduate Medical Education (ACGME)–accredited palliative medicine fellowship programs about substance abuse perception, policies, training, and screening. Thirty-eight programs responded. Policies for screening patients (present at 40.5% of programs), dealing with diversion (present at 27% of programs), and use of a screening tool (present at 32.4% of programs) were reported infrequently. The authors concluded that consensus guidelines specifically addressing substance abuse and diversion for palliative patients are needed.40
Consider another case example, in which a patient presents with well-documented cancer and severe pain associated with widely metastatic malignancy, and an expectation of less than 6 months to live. This patient is currently prescribed high doses of several immediate and sustained-release opioids, as well as other controlled substances. The patient presents with family members requesting a dose increase due to unresolved pain. Review of records from previous prescribers describes past drug abuse that was not reported by the patient and which had been tolerated by the prior prescribers. One clinician may view this as something that should be overlooked due to the ethical issues associated with the diagnosis and prognosis. A different clinician might view this as a serious point of caution that requires investigation, including urine drug screening, to be able to proceed. Faced with the magnitude and implications of the underlying cancer disease process, requiring a urine drug screen may seem to some as completely appropriate or to others as not only unnecessary but perhaps even immoral. A more dramatic version of this dilemma is exemplified by the patient who presents for pain management with extensive metastatic disease and limited life expectancy who admits to current abuse of methamphetamine (or any other illicit drug of abuse). The patient states the high-dose opioid medication being provided is not sufficient to treat the pain despite multiple substantial dose escalations. When confronted about concerns regarding ongoing use of illicit drugs of abuse, the patient states “I’ve been fine using Meth and the painkillers for a long time—why should you care doctor, I am dying anyway.”
The scenarios presented above are not common, but are among countless possible challenges in providing safe pain management for patients with cancer or terminal illness. They underscore the internal struggle of the physician to treat pain without doing harm to the patient and their community. Although the ability to weigh risks and benefits is fundamental to all medical decisions, without specific guidance, weighing risks versus benefits in these dilemmas can be difficult. In some of these cases, attempting to verify the patients’ self-report may be perceived as in direct conflict with the physician-patient covenant, yet trusting the patient may be perceived as in direct conflict with protecting society. Prescribers may be apprehensive about being perceived as heavy handed in following contemporary guidelines for opioid pharmacovigilance that have arisen out of our current epidemic of prescription drug abuse, but are tacitly or specifically detached from the care of patients diagnosed with cancer or terminal illness. Perhaps, in some part, the exclusion of cancer and terminal illness in the most current opioid prescribing guidelines may serve some as a justification for emphasizing the compassionate benefits of opioids over the risks of misuse or abuse to the individual or society. Alternatively, prescribers could also feel rightfully concerned that such an approach may be unsafe, unethical, or even illegal due to prescribing controlled substances in association with real or potentially unmitigated drug abuse.
A prescriber treating a patient with active cancer or terminal illness associated with substance abuse is faced with a dilemma (a choice between equally undesirable alternatives). Drug misuse, abuse, and addiction in cancer and terminal illness challenge the essence of the physician-patient relationship and the physician’s obligation to do no harm. It brings attention to the potentially conflicting and uncomfortable dual responsibilities of the clinician to the individual and society. Current evidence suggests that patients with cancer or terminal illness are at relatively similar risk for misuse, abuse, and addiction compared with the general population.35–37 , 41–43 Aberrancy in this patient population has been noted to escalate suffering, as well as interfere with medical treatments including oncologic care.44 , 45
Undoubtedly, there are many reasons why opportunities to address safety in opioid prescribing for pain associated with cancer and terminal illness have largely been missed throughout the current guidelines that represent best practices from professional and governmental organizations. Likely contributors to this gap include cultural issues related to cancer and dying, as well as compassionate resistance to adding any additional barriers to the care afforded to this special population. Although there are significant issues that differentiate opioid use in this population from that of chronic illness, including ethical principles, the impact of drug misuse, abuse, and addiction is nonetheless significant on the individual and society.
Over the past 10 years, we have learned a great deal regarding the risks of and responsibilities associated with prescribing opioids. The inadequate education of the general medical community around basic knowledge of pain management is now well established.18 , 46 The crisis of excessive opioid prescribing is undoubtedly rooted, in part, in this education gap as well as related to inadequate research and reliance on erroneous data that wrongly suggested opioids are safe when prescribed for pain, and limited clinical resources and reimbursement for treatments other than medications. In addition, the reduced suffering and improved quality of life that was appreciated through liberalizing opioid use in terminally ill patients was overly generalized to patients with chronic pain.
Current guidelines for opioid prescribing, including the most recent CDC guideline for prescribing opioids for chronic pain, largely avoid or expressly exclude treatment of patients with cancer or terminal illness. Moreover, the guidelines that have addressed cancer-associated pain, such as those from the WHO and EAPC, do not provide guidance on how to address misuse, abuse, and diversion and do not operationalize surveillance methods for harm reduction. Evidence suggests that there is limited instruction in safe opioid prescribing practices in palliative care training programs, translating into a paucity of resources applied to the current work force of hospice care agencies.18 , 38–40 , 46 Additional research suggests that our hospice and palliative care programs are ill prepared for identifying and managing opioid misuse, abuse, and addiction.38–40
Despite similar risks for abuse, misuse, and diversion in patients with cancer-associated pain and the general public, reliance on opioid therapy in these patients may be more prevalent than in other chronic illnesses. As oncologic care increasingly succeeds in extending quantity of life, many cancer patients successfully become survivors. Increasingly, many forms of cancer are considered to be chronic illnesses. Survivorship can be burdened with many challenges as patients experience severe, persistent symptoms secondary to the collateral effects of oncologic treatment and other interventions. Clinicians may view these patients as having a chronic illness or residual cancer, each potentially representing different approaches and responsibilities. Vague but real distinctions between safe practice in the care of patients with cancer and chronic pain cloud decisions for prescribers struggling to find a safe harbor for intervening when patients complain of pain and suffering. The American Society of Clinical Oncologists and the CDC released practice guideline that address opioid safety issues, universal precautions, for Chronic Pain in Survivors of Adult Cancers.1 , 47 However, these guidelines do not address care of the patient with active cancer or terminal illness.
Considering the substantial challenges for prescribers involved in navigating critical decisions for patients in pain associated with treatable or incurable cancer, or with limited time left in their life, it is important that these issues are openly examined and discussed. Issues around medical efficacy, safety, compassion, personal morals, and professional ethics, among others, compound the complexity of care. Questions remain regarding when and where in the pain treatment algorithm more sophisticated assessments should guide pain therapy toward opioid-sparing options. Research is greatly needed to better understand the bioethical dilemmas associated with misuse, abuse, and addiction in the population with cancer and terminal illness.
Currently, there is stark contrast between recent authoritative guidance on prescribing opioids for acute and chronic pain and the paucity of discourse, if not guidelines, on the care of patients with active cancer or terminal illness. This leaves a gap from which prescribers must infer a standard of care that can range from an emphasis on maximizing individual comfort to avoidance of risk to society. Professional, federal, and state stakeholder organizations are in a position to address this gap. For instance, the National Academy of Medicine (NAM) recently released its review of pain management and the opioid epidemic,48 and previously studied pain in America,18 as well as quality of life and individual preferences near the end of life.49 An NAM study of pain, opioids, and end-of-life care in America would tie together these prior seminal reports. Despite the sensitivities associated with addressing the medical, social, and ethical issues involved in safe use of opioids for patients with active cancer or terminal illness, clinicians and patients will be best served if governmental and professional stakeholder organizations endeavor to study and understand these issues. Irrespective of the direction provided, updated approaches and clarity of expectations in the care of these patients are needed.
Name: David J. Copenhaver, MD, MPH.
Contribution: This author helped research and edit the manuscript and also authored the manuscript.
Name: Nicolas B. Karvelas, MD.
Contribution: This author helped research and edit the manuscript and also authored the manuscript.
Name: Scott M. Fishman, MD.
Contribution: This author helped research and edit the manuscript and also authored the manuscript.
This manuscript was handled by: Honorio T. Benzon, MD.
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