Version May 2024
INTRODUCTION — Pain is highly prevalent in the cancer population. Virtually all patients with malignant disease experience recurrent episodes of acute pain, which may accompany surgery, invasive procedures, or complications, such as a pathological fracture. In addition, chronic pain that is severe enough to warrant opioid therapy is experienced by 30 to 50 percent of patients undergoing active antineoplastic therapy and by 75 to 90 percent of those with advanced disease [1,2].
The causes of chronic pain are diverse in this population, and both prevalence and severity vary with the type of neoplasm, stage and extent of disease, prior treatment, comorbidities, and other factors. Tissue injury produced by the neoplasm is the primary etiology in about three-fourths of patients with chronic cancer pain, and the remainder have pain related to the late effects of antineoplastic therapy or to painful comorbidities. (See "Assessment of cancer pain".)
Opioid therapy is the first-line approach for moderate or severe chronic cancer pain. While opioids are effective analgesics, they are potentially abusable drugs. The public health consequences of opioid abuse drive the imperative that all clinicians assume responsibility for risk management when these drugs are prescribed for legitimate medical purposes. (See "Cancer pain management with opioids: Optimizing analgesia".)
This topic review will cover the general principles of cancer pain management and provide an overview of risk assessment and management in patients treated with opioids. An overview of assessment of cancer pain, a review of specific cancer pain syndromes, the clinical use of opioid analgesics, non-opioid analgesics (including adjuvant analgesics) and nonpharmacologic methods of cancer pain management are covered elsewhere. (See appropriate topic reviews.)
THE PROBLEM OF UNDERTREATMENT — Adequate pain relief can be achieved in more than 70 percent of patients when well-accepted opioid treatment guidelines for cancer pain are followed [3-8]. Given that most recommended therapies for cancer pain are within the scope of both specialty and primary care medical practice, the treatment of cancer pain should be viewed as a best practice for all medical disciplines involved in the care of this population.
Unfortunately, the availability of effective therapy and updated guidelines from reliable leading societies has not eliminated the problem of undertreatment of cancer pain [9-15]. A year 2014 systematic review concluded that while there was a decrease in undertreatment between 2008 and 2013 of approximately 25 percent (from 43 to 31 percent), approximately one-third of patients with cancer-related pain still do not receive pain medication proportional to their pain intensity [14]. A systematic review of 66 studies published through 2020 confirmed a decline in undertreatment over time, but noted that the literature continues to demonstrate that about 40 percent of cancer patients receive analgesic treatment that is inconsistent with recommendations that are based on pain severity [16]. At the individual level, the odds of undertreatment appear to be substantially higher for underrepresented populations [12].
The causes of undertreatment are multifactorial and reflect the combined effects of clinician-, patient-, and system-related barriers [9,17-21]:
●Clinicians often have inadequate knowledge and skills, or attitudes that minimize the importance of pain management. They may be reluctant to prescribe drugs due to concern about side effects or a fear of hastening death through aggressive pain control.
●Patients may underreport pain because of stoicism, a desire to be liked, or concerns about distracting the clinician from antineoplastic treatment. In addition, when opioid therapy is provided, therapeutic nonadherence is believed to be common, perhaps due to fear of addiction or the development of side effects.
●System-wide impediments to optimal analgesic therapy may include financial concerns (eg, lack of health care insurance coverage, inability to purchase drugs), a limited number of specialists in pain management or palliative care, and an incentive structure in the health care system that does not encourage clinicians to manage pain as a priority.
●In the United States, there are racial and ethnic disparities in the assessment and management of pain using opioids, which may reflect the problems of implicit bias or systemic racism impacting the availability of opioid therapy in diverse communities [22-25].
●Also specific to the United States several population-level studies suggest that regulations and guidelines that appeared after 2010 and were intended to reduce opioid prescribing in populations with non-cancer pain may have unintentionally led to a decline in appropriate opioid use for moderate to severe cancer pain [26-30].
Uncontrolled pain results in unnecessary suffering, decreased ability to cope with illness, interference with activities of daily living, and extended or repeat hospital admissions [19,31]. Uncontrolled pain may also delay or disrupt anticancer treatment, compromising its effectiveness.
Given the profound impact of uncontrolled pain on all aspects of life, and the prevalence and complexity of undertreatment, clinicians must be attuned to the possibility that poorly controlled pain is being under-reported, and that it may be the result of poor access to care, under prescribing, and/or nonadherence. The risk should be assumed to be particularly high in vulnerable populations, including underrepresented groups, the poor or uninsured, patients with a history of chemical dependency or other serious psychiatric disease, and those living in low- and middle-income countries [32]. Awareness of undertreatment and the willingness to confront its causes is a first step toward improving outcomes.
PAIN MANAGEMENT WITHIN THE CONTEXT OF PALLIATIVE CARE — Among individuals with active cancer, pain is best considered as a domain within the broader context of palliative care. Palliative care is an interdisciplinary therapeutic approach that focuses on the comprehensive management of the physical, psychological, social, and spiritual needs of patients with serious or life-threatening disease and their caregivers [33].
The overriding goal of palliative care is to reduce the suffering and illness burden of the patient and caregivers throughout the course of a progressive illness. Palliative care focuses on diminishing the burden of illness from the time of diagnosis to death. Effective palliative care considers the needs of both the patient and their caregivers, viewing the caregivers as the unit of care. It addresses the nature of grief before the death and into the bereavement period that follows.
Generalist-level palliative care (primary palliative care) can and should be provided by all clinicians who are involved in the ongoing care of the patient with a serious life-threatening illness and their caregivers. Consultation with clinicians who are specifically trained in palliative care (specialist palliative care) may be appropriate whenever the complexity of problems warrants a referral and is typically sought when the end of life is perceived to be near. Specialty palliative care services are most available in high-income countries, including the United States. The availability of specialty palliative care in low income countries is quite limited. (See "Benefits, services, and models of subspecialty palliative care" and "Palliative care and hospice outside of the United States".)
Palliative medicine specialists work in interdisciplinary teams or develop networks that facilitate the involvement of other professionals when needed. Most hospitals in the United States now have some type of institution-based palliative care consultation program [34]. Home-based specialist palliative care, available to patients living in their own homes or in skilled nursing facilities, is now mostly provided by hospice agencies in the United States. Hospice care is a benefit of Medicare and Medicaid, and is also supported by most commercial insurers. Patients are eligible for the government benefit if a clinician employed by the hospice agency certifies that it is more likely than not that the patient's prognosis is six months or less if the illness runs its expected course. Community-based palliative care that is distinct from hospice is gradually emerging but still has very limited availability. At present, hospice programs provide most cancer patients with specialist palliative care at the end of life [35]. (See "Palliative care delivery in the home".)
From the perspective of palliative care, pain assessment and management are major aspects of the care plan that focuses on many domains related to quality of life. Pain management should be integrated with other strategies that are being used to address other key goals, such as the relief of other symptoms (eg, dyspnea, fatigue), coordination of care across sites, appropriate advance care planning, and management of caregiver distress.
Like pain management itself, the broader clinical concerns that constitute palliative care should be considered a best practice for all clinicians engaged in the treatment of patients with cancer. At a generalist level, this typically takes the form of multidimensional assessment and intervention in a variety of domains related to preserving function, improving adaptation, and maintaining quality of life. When the clinical issues are complex, particularly when pain is difficult to control or accompanied by other concerns, referral to a palliative care specialist is appropriate.
Pain specialists may or may not have expertise in palliative care or a professional focus on cancer pain. Because pain specialists vary in background, training, interest and accessibility, the clinician seeking help for a patient with challenging pain should ensure that a pain specialist has experience and capability in cancer pain before making a referral.
Regardless of the treatment team, assessment of the patient with cancer pain requires a clear understanding of the goals of care in relation to the broader treatment plan. As an illness advances, the goals of the patient and their caregivers may evolve, gradually shifting to an emphasis on comfort above all else. As this occurs, decisions about therapy and the information provided to the patient and caregivers may change. Modifying the care plan as goals of care shift requires ongoing communication, education, and support of the patient and their caregivers. (See "Discussing goals of care".)
GENERAL PRINCIPLES OF PAIN MANAGEMENT — An effective strategy for cancer pain management is predicated on several broad principles:
●A detailed assessment of the pain should be performed initially; careful reassessment is indicated whenever a change occurs. The initial assessment of the patient with cancer pain always includes a history and examination, and often requires imaging or laboratory tests. The approach may be conceptualized as collecting data sufficient to characterize key elements of the pain (see "Assessment of cancer pain"):
•A specific pain syndrome, if one can be defined (eg, multifocal bone pain or malignant brachial plexopathy) (see "Overview of cancer pain syndromes")
•The inferred pathophysiology of the pain (eg, neuropathic pain related to dysfunction of the nervous system, or nociceptive pain related to ongoing tissue injury) (see "Assessment of cancer pain", section on 'Inferred pathophysiology and treatment implications')
•The etiology of the pain (ie, its relationship to the disease or another factor)
•The extent of cancer and the plan for further cancer treatment
•The goals of care relative to pain management
•Other "palliative care concerns," including management of symptoms other than pain. Symptom burden tends to be high in patients with cancer-related pain and recognizing and managing symptoms other than pain may improve quality of life and functional status [36].
●The second principle recognizes that pain may be addressed by disease-modifying antineoplastic therapy and other interventions directed against the etiology of the pain. Treatments that address the underlying etiology of pain, such as radiation therapy, surgery, or in some cases, chemotherapy, can be integrated into a broader plan of care for symptom control. Treatment of cancer-related pain usually requires close consultation with an oncology specialist, who can provide the necessary information about the availability of antineoplastic therapy.
●Whether or not primary disease-modifying therapy is possible, a large proportion of patients with pain due to active cancer require symptomatic treatment. Beginning in the early 1980s, a worldwide consensus has evolved that considers opioid-based pharmacotherapy as the mainstay approach for the symptomatic treatment of cancer patients with active disease and pain that is moderate to severe [4,5,37].
Patients with cancer pain that is generally mild should first be treated with acetaminophen or a nonsteroidal anti-inflammatory agent (NSAID). This analgesic may be combined with an adjuvant drug that provides additional analgesia (ie, a so-called "adjuvant analgesic," such as an analgesic antidepressant drug for neuropathic pain), treats a side effect, or manages a coexisting symptom. A low-dose opioid may be required for pain that is persistent or increasing [38]. (See "Cancer pain management: Role of adjuvant analgesics (coanalgesics)".)
The quality of the evidence to support benefit from opioids in cancer pain is surprisingly low. An analysis of Cochrane reviews (152 studies, including 13,524 patients) found that the amount and quality of the evidence were very low; most studies were at high risk of bias from several sources, including small study size and short follow-up [39]. Based on the limited data available, the authors concluded that 19 out of every 20 people with moderate to severe cancer-related pain who are given opioids and can tolerate them should have that pain reduced to mild or no pain within 14 days. Most people will experience adverse events, and between 1 and 2 of every 10 patients treated with opioids will find these adverse effects to be intolerable, leading to a change in treatment.
Evidence-based and consensus-based clinical guidelines now exist for managing cancer pain, and competency in cancer pain management requires a more detailed understanding of the principles of appropriate drug selection and dosing [4,5,37,38,40-43]. Guidelines for use and selection of opioids for management of cancer-related pain are discussed in detail elsewhere. (See "Cancer pain management with opioids: Optimizing analgesia".)
There are also now many other options for pain control in addition to opioids, which are outlined in the table (table 1). Adjuvant analgesics, as well as interventional, rehabilitative, psychological, and integrative approaches to pain control are discussed in detail elsewhere. (See "Cancer pain management: Role of adjuvant analgesics (coanalgesics)" and "Cancer pain management: Use of acetaminophen and nonsteroidal anti-inflammatory drugs" and "Interventional therapies for chronic pain" and "Rehabilitative and integrative therapies for pain in patients with cancer".)
RISK ASSESSMENT AND MANAGEMENT FOR PATIENTS RECEIVING OPIOIDS — Opioids are potentially abusable drugs and safe prescribing requires consideration of the risks associated with drug abuse, addiction, and diversion to the illicit marketplace. Their potential for abuse and addiction results from the "brain reward" they induce in biologically predisposed individuals, which is mediated through dopamine pathways in the brain. The potential for harm to the individual and the important public health consequences of opioid abuse drive the imperative that all clinicians assume responsibility for risk management when potentially abusable drugs like opioids are prescribed for legitimate medical purposes. (See "Opioid use disorder: Epidemiology, clinical features, health consequences, screening, and assessment".)
The ability to assess and manage the risk of abuse, addiction, and diversion is one of the foundations to safe and effective opioid prescribing. The importance of risk management during the treatment of cancer pain, complementing the broad consensus that opioid-based drug therapy is the mainstay approach for the treatment of moderate or severe chronic cancer pain, is underscored the prevalence of opioid use disorder in populations with cancer-related pain, estimated to be approximately 8 percent [44]. (See 'Risk of aberrant opioid behavior in cancer patients' below.)
Risk assessment requires an understanding of the laws and regulations with which prescribers must comply. All medications with the potential for abuse and addiction are regulated [45]. In the United States, these drugs are designated "controlled substances" under a federal law known as the Controlled Substances Act (CSA), which places controlled prescription drugs in one of five "schedules" based on abuse liability (table 2). Under the CSA, most opioids used for cancer pain management are schedule II, which indicates a high liability for abuse and diversion. Both federal and state laws are in force to regulate all scheduled drugs, particularly those in schedule II. Clinicians are required to know and comply with these laws.
Impact of the opioid overdose crisis
Regulatory issues — Drug overdose, principally due to opioids, is rising in many developed countries; in the United States, drug overdose has been the leading cause of injury-related death since 2009, with opioid overdose alone the leading cause in 2016 [46]. This rising rate of opioid overdose in the United States was related to prescription opioids until 2012. Subsequently, prescription opioid abuse and overdose declined, but opioid overdoses continued to rise as a result of illicit drugs, mostly heroin and illicit fentanyl. (See "Prevention of lethal opioid overdose in the community", section on 'Epidemiology'.)
With increasing prescription drug abuse and opioid-associated overdose deaths, both the federal government and state governments have taken additional steps to regulate opioids. In response to a mandate by the United States Congress, the US Food and Drug Administration (FDA) has created two Risk Evaluation and Mitigation Strategies (REMS), one for extended-release and long-acting opioids including transdermal preparations and methadone analgesics, and one for transmucosal immediate-release fentanyl formulations [47].
The prescriber components of the REMS program for the long-acting/extended-release preparations (ie, prescriber education and patient counseling) are strongly encouraged, but not mandatory. However, for transmucosal fentanyl preparations, the REMS requires registration of outpatient prescribers, pharmacies, distributors, and patients in the Transmucosal fentanyl REMS access program. Prescribers may not prescribe transmucosal fentanyl for outpatient use until they have completed enrollment in the REMS program and a knowledge assessment. Furthermore, the REMS for transmucosal fentanyl includes mandatory statements signed by the patient and prescriber, which outline patient and clinician responsibilities for safe opioid use (although it is not clear that the guidelines are being followed [48]). The approved REMS are available on the FDA website.
It is unclear whether implementation of these REMS, especially for the extended-release/long-acting preparations, has or will curb the potential for abuse with this group of drugs [49], and the REMS are just one of many changes happening at the federal and state levels that are intended to reduce drug abuse.
Balancing regulation with access to adequate analgesia — The intent of the new laws and regulations described above is to reduce opioid abuse, and is widely supported by clinicians, regulators, and those in law enforcement. Clinicians have raised concerns, however, that the effort to reduce risk could create barriers to prescribing, the result of which will be more unrelieved pain, challenging the ability of oncologists and palliative care clinicians to provide compassionate care that includes adequate pain relief. As noted, there is evidence that regulations to curb opioid abuse might reduce legitimate access by patients with cancer who need opioids for chronic pain, including those near end of life, and increasing the burden of cancer-related pain [26-30,50]. As examples:
●In an analysis of the United States Medicare prescription claims database, between 2013 and 2017, the national opioid prescribing rate declined by 21 percent among oncologists and by 23 percent among non-oncologists, and during this five-year period, 43 states experienced a decrease in opioid prescribing among oncologists, which in five states was more than the decreased rate of opioid prescribing among non-oncologists [50].
●In another study, between 2007 and 2017, the proportion of Medicare fee-for-service decedents with poor prognosis cancers receiving one or more opioid prescriptions near end of life declined from 42 to 35.3 percent, the proportion receiving one or more long-acting opioid prescriptions declined from 18.1 to 11.5 percent, and the median daily dose fell 24.5 percent from 85.6 to 64.6 morphine milligram equivalents per day (MMEDs) [28]. Simultaneously, the proportion of patients with pain-related emergency department visits increased 50.8 percent, from 13.2 to 19.9 percent, suggesting that end of life cancer pain management may be worsening over time.
Achieving a balance in drug regulation between the need to reduce abuse and the need to maintain access to essential medications is very challenging, and the concerns that REMS and other approaches will increase the reluctance of oncologists and other clinicians to use opioids generally, or formulations like transmucosal fentanyl specifically, are legitimate.
The following guidelines have addressed these issues:
●Principles for balancing the appropriate, safe, and effective use of opioid therapy for pain with the need to curb misuse and abuse have been addressed in a 2016 policy statement on protecting access to opioid treatment for cancer-related pain from the American Society of Clinical Oncology (ASCO). The ASCO principles for opioid access are outlined in the table (table 3) [51], and highlight the need to replace the historical tendency to ignore or minimize the importance of risk assessment and management when using opioids for cancer pain [52] with appropriate vigilance and best practices in risk management.
ASCO also has a guideline for management of chronic pain but focuses on survivors of adult cancers and not patients with active cancer [53].
●In the United States, influential guidelines for opioid prescribing were published by the Centers for Disease Control and Prevention (CDC) in 2016. Although these guidelines specifically excluded treatment of patients with cancer or other terminal illness [54], some prescribers presumably extrapolated the guidance to this population and some insurance payers inappropriately use it to deny opioid coverage for the cancer populations. Many states also have enacted formal legislation limiting the duration and/or dose of opioid prescriptions, and although the majority explicitly exempt patients with cancer-related pain, exemptions are broadly applied with few states providing specific guidance for prescribing for cancer-related pain [55]. In response to these issues, the CDC issued a clarification stating that its recommendations were not intended to deny clinically appropriate treatment to patients who suffer acute or chronic pain from conditions such as cancer [56].
Furthermore, in 2022, the CDC issued a detailed update to the 2016 clinical practice guideline updating the 2016 publication [57]. This guideline states that its recommendations do not apply to the population with cancer pain, or pain due to sickle cell disease, or to populations receiving palliative or end-of-life care. The CDC has not issued a separate set of guidelines for opioid prescribing in cancer patients. Yet, clinicians caring for cancer patients may benefit from becoming familiar with the new guidelines, which are evidence-based and describe best practices in risk assessment and management that may be extrapolated for use in the cancer population. (See "Use of opioids in the management of chronic non-cancer pain", section on 'Evaluation of risk prior to initiating therapy'.)
●Updated evidence-based guidelines for treating patients with cancer-associated pain from the European Association for Palliative Care (EAPC) [5] do not address the major safety concerns that face contemporary prescribers, lacking guidance on how to address misuse, abuse, and diversion, and what, if any, surveillance methods are advised for harm reduction.
●Consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) [4] recommend routine assessment of risk factors for aberrant opioid use and monitoring for aberrant behaviors or evidence of diversion during therapy; however, the exact details with regard to what diagnostic tests (eg, urine drug screen) to use and how often to use them are not addressed.
Risk of aberrant opioid behavior in cancer patients — To date, few studies have assessed the use of practice-level approaches for identifying, evaluating, or managing opioid misuse, abuse, and addiction in patients with cancer pain [58-60], and there are several gaps that exist among the available clinical practice guidelines [61]. These studies suggest that oncology practices and programs that manage cancer patients with advanced illness (eg, hospice or palliative care) are ill prepared for identifying and managing opioid misuse, abuse, and addiction. A survey of Accreditation Council for Graduate Medical Education (ACGME)-accredited palliative medicine fellowship programs observed that most programs do not have policies or training opportunities focused on screening patients for abuse or dealing with diversion [60].
However, efforts to improve practices that identify, assess, and manage aberrant opioid behavior in patients with cancer-associated pain are justified by its prevalence [44,62-65]:
●In one study of 432 patients with cancer-associated pain treated with opioids by palliative care specialists, 18 percent were using opioids in a nonprescribed manner to cope with the various stressful events associated with the diagnosis and management of their cancer [63].
●Similarly, in an analysis of 1554 consecutive patients with cancer receiving opioids for cancer pain referred to a single cancer center supportive care program, nonmedical opioid use behavior was documented in 19 percent within a median duration of eight weeks after initial supportive care clinic consultation [64]. Factors independently associated with nonmedical opioid use behavior included marital status (single or divorced), Screener and Opioid Assessment for Patients with Pain (SOAPP) questionnaire score >7 [66], higher levels of pain severity, and morphine equivalent daily dose >50 mg. (See 'Risk assessment' below.)
●A year 2022 systematic review and meta-analysis of 15 studies published during the two decades prior to 2020, identified a prevalence of opioid use disorder in populations with cancer-related pain of 8 percent (95% CI 1-20 percent) [44].
Aberrant opioid use in the population with cancer pain can produce adverse consequences for the individual, including increased symptom distress or a reluctance to accept recommended oncologic care. The relationship with clinicians and other professional caregivers can be compromised, and the clinician in particular may experience uncertainty and distress while trying to balance the importance of pain control with the potential for harm to the patient or the community.
Many experts endorse the view that the decision to prescribe an opioid for pain management always should be preceded by careful risk assessment. Although the risk of aberrant drug-related behaviors is minimal or nil in many clinical circumstances (eg, acute pain management in a hospital setting or treatment of pain at the very end of life), there are many times that the risk cannot be trivialized and a careful strategy is necessary to preempt or minimize problems.
Risk assessment requires a clear understanding of the clinical presentations of the phenomena related to the abuse liability of opioid drugs. These phenomena include abuse, addiction, and diversion [67]. (See 'Risk assessment' below.)
Drug abuse versus addiction and physical dependence — The term "drug abuse" refers to the use of a drug in a manner that deviates from medical, legal, and social standards. Prescription drugs are abused when taken in any manner that was not prescribed. In the United States, indicators of prescription opioid abuse increased at an alarming rate between the early 2000s and the mid-2010s (see "Prescription drug misuse: Epidemiology, prevention, identification, and management", section on 'Prescription drug misuse'). As noted, a key indicator, prescription opioid overdose, peaked in 2012 and declined thereafter, to be replaced by a rise in the rate of illicit opioid overdose.
Addiction is a disease with a strong genetic component that is defined by aberrant drug-taking behavior, characterized by craving, loss of control, compulsive use, and continued use despite harm. The biologic propensity toward addictive disease affects a small minority of the population, probably no more than 10 percent. A personal or family history of alcohol or drug abuse may reveal such a propensity, and individuals with such a history should be considered high risk for problematic drug-related behavior during treatment with an opioid or other potentially abusable drug.
A personal history and family history with no indication of alcohol or drug abuse does not mean that the genetic predisposition to addiction is absent. Although the risk is relatively lower, it is possible that exposure to therapeutic opioids can trigger an addictive disorder de novo. (See "Risky drinking and alcohol use disorder: Epidemiology, clinical features, adverse consequences, screening, and assessment" and "Opioid use disorder: Epidemiology, clinical features, health consequences, screening, and assessment".)
Addiction must be distinguished from the physiologic phenomena of physical dependence and tolerance. Physical dependence is defined solely by the occurrence of withdrawal symptoms after abrupt dose reduction or the administration of an antagonist. Tolerance is defined solely by the drug-induced loss of an effect over time. Although these phenomena presumably occur commonly as addiction evolves, neither are necessary for addiction to occur, and equally important, neither means that abuse or addiction is occurring.
Diversion — Diversion is a legal concept, referring to the distribution of a drug into the illicit marketplace. Physicians are required to stop prescribing when there is a strong likelihood that diversion of prescribed drugs is occurring. In the United States, this legal constraint is codified in the Federal Controlled Substances Act, which states that prescribing of a controlled prescription drug (ie, one with the potential for abuse) is legal only if it is for a legitimate medical purpose, and performed within the course of usual professional practice [68]. (See "Prescription drug misuse: Epidemiology, prevention, identification, and management", section on 'Controlled substances'.)
In contrast to the requirement that prescribing cease if diversion is occurring, the law states that prescribing may continue legally in the context of suspected abuse or addiction if appropriate medical actions are being taken to stop the behavior, regain control over the prescribing, and manage the medical and psychiatric condition of the patient. Great care must be taken, however, because clinicians are subject to review under medical practice regulations, as well as drug laws, and must prescribe within conventionally accepted standards. When aberrant behaviors occur and cannot be promptly and effectively managed, consultation with a specialist in addiction medicine should be considered to appropriately diagnose and manage the nature of a drug-related problem. High-risk patients may warrant co-management, with consultation before a commitment is made by the prescribing to continue opioid therapy on a long-term basis. In some cases, referral to a pain medicine or palliative medicine specialist also can clarify best practices and next steps. Careful documentation is mandatory.
Risk assessment — With an understanding of these phenomena, clinicians can stratify the estimated risk of problematic drug-related behavior in individual patients, and judge whether treatment with a controlled prescription drug can proceed, should proceed without assistance from a specialist, or proceeds in tandem with risk management approaches that emphasize adherence monitoring and control. General principles of risk assessment and risk management for patients receiving opioids for treatment of cancer pain are outlined in the table (table 4).
Although numerous questionnaires have been developed for the prediction of risk (eg, the CAGE questionnaire, the Opioid Risk Tool [ORT], and the Screener and Opioid Assessment for Patients with Pain [SOAPP]), none has been adequately validated in cancer patients or is in widespread use [65,69-78]. A systematic review of 18 studies [65] evaluated found that the use of the CAGE, ORT, or SOAPP, and the use of urine drug screening, could identify opioid abuse, with rates that varied by the methods employed in the studies. (See "Use of opioids in the management of chronic non-cancer pain", section on 'Risk assessment tools'.)
In clinical practice, a relatively higher risk of problematic drug-related behavior during treatment with an opioid or other controlled prescription drug should be suspected if the patient has one or more of the following [4,65,67,79-81]:
●A personal history of alcohol dependence or drug abuse.
●A family history of alcohol or drug abuse.
●A major psychiatric disorder (including anxiety, depression, personality disorder, attention deficit hyperactivity disorder [ADHD], posttraumatic stress disorder [PTSD], bipolar disorder or schizophrenia).
●Patients with a history of sexual abuse victimization may be at increased risk for opioid abuse/misuse.
●Patients with a history of legal problems or incarceration.
●Medication-assisted treatment for substance use disorder. Patients receiving treatment for addiction should be encouraged to continue with therapy and pain management should be carried out in coordination with an addiction specialist.
The presence of any of these factors indicates an elevated risk for problematic drug-related behavior. A number of questionnaires are available to assist in screening for unhealthy use of alcohol or other drugs. (See "Screening for unhealthy use of alcohol and other drugs in primary care", section on 'Unhealthy alcohol use' and "Screening for unhealthy use of alcohol and other drugs in primary care", section on 'Unhealthy alcohol and other drug use'.)
Other factors, such as younger age, smoking history, social isolation or involvement with a drug abuse subculture, a history of multiple automobile accidents, financial distress, and inability to maintain employment, also may be important to consider when stratifying risk of aberrant drug-related behaviors. (See "Prescription drug misuse: Epidemiology, prevention, identification, and management".)
Notably, the absence of risk factors does not ensure that an individual will be adherent over time or exclude a risk of abuse or addiction. Risk factors overall have low sensitivity for identifying individuals who will develop opioid problems.
All cancer patients who are prescribed controlled prescription drugs must be carefully monitored during therapy for nonadherence—behaviors that might suggest aberrant nonmedical use (table 5). Those who are at relatively higher risk should be monitored more rigorously. While there are tools to assist with screening and diagnosis during therapy (eg, the Current Opioid Misuse Measure [COMM]) [69,82-86], none are adequately validated, none have been studied in cancer patients, none can replace a careful substance use and psychiatric history, and none can be recommended for routine use.
When screening questions suggest that a cancer patient may be at risk for problematic drug-related behavior, the prescribing clinician should communicate this concern and attempt to engage the patient in a plan for adherence monitoring. Clinicians may feel unprepared for this conversation [87] and worry that the therapeutic alliance could be ruptured by the patient's perception that the clinician lacks trust, is threatening the withholding of needed treatment, or even is suggesting that the patient could be discharged from care. The following are points to remember when first communicating about the results of the screening:
●Remember that a proactive and appropriate response, with documentation, is best practice.
●Recognize that the communication may generate anger, anxiety, or shame on the part of the patient, and that the interaction may become emotional and possibly conflictual. Adopt a nonjudgmental stance (this is all about balancing risks and benefits of treatment), prepare to allow emotions to be expressed and to de-escalate tension by pointing to the rationale for the clinician's actions and the viability of next steps, and realize that the messages that must be conveyed may need to be repeated until the patient demonstrates understanding.
●Have a plan for next steps at the time of the discussion (eg, to request regular urine drug screens or a treatment agreement), so that the patient's concerns about the availability of treatment can be addressed immediately.
●Begin the discussion by describing the finding that indicates risk level and stating that this finding means that a clinician must put in place a plan to monitor the patient carefully. Explain that monitoring means obtaining information that confirms that the patient is taking the medication exactly as prescribed and is neither taking other medication without telling the doctor nor abusing drugs or alcohol. Also state that monitoring is not about a lack of trust but, rather, is a practice that clinicians must do in order to act in the patient's best interest, both in terms of providing access to treatment and ensuring that treatment is provided in a safe and effective way.
●Explain the type of nonadherence monitoring that is planned, and state that it may change over time.
●Try to elicit understanding of the elements of the plan, emphasizing the importance of adherence (following instructions exactly).
Depending on the nature of the interaction, it may be useful to also emphasize that treatment will not be able to proceed if the plan for monitoring is not followed or the patient is unable to take the medication exactly as prescribed.
Risk management — Competent risk management empowers the clinician to use controlled prescription drugs as broadly and as aggressively as medical indications require.
When the risk of aberrant drug-related behavior is assessed as low (as it is in most patients with cancer pain), prescribing of an opioid can proceed with simple and straightforward strategies for adherence monitoring and controlling drug use. The medical record should document that prescribing is occurring in the context of a therapeutic relationship and for a specific medical problem that has been evaluated in a routine manner (history, examination, appropriate formulation of diagnosis). Reassessment should be performed or planned at periodic intervals to ensure that the medication remains necessary and adequate. There should be documentation of each prescription that is written for a controlled substance.
Role of urine drug testing — The role of random urine drug testing (UDT) for patients at low risk for aberrant drug-related behavior is controversial. Random UDT is an effective risk monitoring tool during chronic opioid therapy, and it has been endorsed in numerous opioid prescribing guidelines for chronic noncancer pain. (See "Urine drug testing for patients with chronic pain".)
However, there is very limited evidence to guide the integration of random UDT into routine cancer pain management, even though rates of aberrant opioid behavior have been reported to be almost 20 percent in some populations. (See 'Risk of aberrant opioid behavior in cancer patients' above.)
At least one study from the supportive care center of a major cancer center concluded that random urine drug testing identifies abnormalities earlier than the use of targeted urine drug testing (ie, testing on the basis of an estimation of the risk of nonmedical opioid use) [88]. In this study, excluding marijuana, 15 percent of the random group had positive UDT, compared with 37 percent of the targeted group. It took a shorter time from the initial supportive care consultation to detect one or more abnormalities in the random group (median 130 versus 274 days).
These studies suggest that risk assessment in some populations of cancer patients, specifically those expected to have a relatively high prevalence of aberrant behavior, may be improved by UDT, including random UDT [89]. Decisions about whether to integrate the use of drug screening into routine risk assessment should be individualized and consider the population, the clinical resources available, and the effectiveness of other types of adherence monitoring.
Managing higher-risk patients — Patients who are considered to be at relatively higher risk for aberrant drug-related behavior should have additional "control measures" incorporated into therapy (table 4) [67,80,90,91]. As an example, a younger patient with an indolent metastatic osteosarcoma who has a history of polysubstance abuse and admits to ongoing use of marijuana might be managed in any of the following ways:
●Frequent prescriptions with small quantities.
●A signed opioid agreement stipulating the rules about early refills and other potential problems, including active substance abuse, sharing medication with others, and suspected diversion [91].
●Periodic urine drug testing to ensure abstinence from non-prescribed controlled prescription drugs and drugs of abuse [92]. However, whether to test for marijuana and other cannabis products as a component of a UDT is controversial, and existing guidelines lack recommendations on this issue. In the United States, cannabis is still illegal at the Federal level, but legal in many states for medicinal and/or recreational use. This subject is discussed in detail elsewhere. (See "Urine drug testing for patients with chronic pain".)
●Given concern about street value and abuse liability, the decision might be made to offer treatment with an opioid that has a long duration of action and a lower abuse potential (eg, methadone), rather than the more highly abused ones, such as long-acting oxycodone (Oxycontin), hydrocodone, and hydromorphone. Fentanyl is highly abused and is a driver of continued high rates of opioid overdose [47], but transdermal fentanyl is not highly abused; clinicians must use their best judgment in deciding whether to prescribe transdermal fentanyl to a patient at high risk.
The use of abuse-deterrent formulations of opioids, which are designed to prevent unintended routes of administration while retaining efficacy with oral administration for legitimate pain relief, is controversial. The specific issues associated with their use are discussed in detail elsewhere. (See "Abuse deterrent opioids".)
●The decision may be made to offer no additional short-acting opioid drug for breakthrough or incident pain, again because of the assumption that these agents are relatively more likely to be abused.
In addition, clinicians should discuss safety strategies (eg, lock boxes) with patients to minimize the potential for involuntary diversion, which occurs when a controlled substance is stolen from a patient without their knowledge. This happens more frequently in patients with unstable housing or caregiver dynamics [91].
In some cases, no additional safety measures beyond routine precautions are needed even when risk factors exist because the severity of the disease or the setting of treatment is such that the likelihood of problematic behaviors is essentially zero. It is best if this understanding is documented in the medical record.
General principles of risk management during opioid treatment for pain are outlined in the table (table 4).
Preventing lethal overdose — We recommend all patients regularly taking opioids for cancer-related pain maintain a supply of naloxone for opioid reversal. Health care professionals should educate patients and their families how to use naloxone in case of an opioid overdose. Over the counter naloxone nasal spray was approved by the FDA in 2023. Intramuscular and subcutaneous forms are also available through prescription.
Patients receiving opioids for chronic cancer pain may develop an opioid use disorder, or their opioids may be stolen or given to a family member or friend who has an opioid use disorder. Individuals with an opioid use disorder are at high risk for premature death from opioid overdose, which is a growing problem in the United States and elsewhere.
Overall, rates of opioid use disorder, opioid-related hospitalizations, and opioid overdoses among patients with cancer appear to be relatively low, although they may be increasing [93-95]:
●In an analysis of data using the United States National Inpatient Sample (NIS) of the Healthcare Cost and Utilization Project (HCUP), among over 25 million hospitalizations overall for patients with cancer between 2006 and 2014, a little over 14,000 were opioid related (0.06 percent), most of which were for non-heroin opioid poisoning [93]. Factors associated with opioid-related hospitalizations in cancer patients were consistent with established risk factors in the non-cancer population (and included drug abuse, depression, and psychotic disorder).
●In a second analysis of data from the linked SEER/Medicare database on 69,889 individuals who were diagnosed with stage I to III breast, colorectal, or prostate cancer at age 66 to 89 between 2008 and 2013, and compared with 125,007 noncancer controls matched for age, sex, and SEER region, colorectal cancer survivors had 2.3 times higher odds of an opioid overdose compared with matched controls (adjusted odds ratio [OR] 2.33, 95% CI 1.49-3.67) [95]. Overdose risk was greater in those with more advanced disease, no prior opioid use, and preexisting mental health conditions.
●At least some data derived from the US Healthcare Cost and Utilization Project Nationwide Emergency Department Sample suggest that emergency department visits for opioid overdoses among patients with cancer doubled between 2006 and 2015 [96].
Education about risks of opioid overdose and the prescription of naloxone to opioid users, caregivers, and others have prevented lethal overdoses. Although rates of naloxone co-prescribing appear to be low overall in the United States [97], some states mandate naloxone co-prescribing for patients receiving opioids at doses of 90 or 100 morphine milligram equivalents (MMEs) per day [98,99]. In July 2020, the US Food and Drug Administration issued a safety communication that health care professionals should discuss the availability of naloxone with all patients when prescribing opioid pain relievers, and consider prescribing it to patients who are at increased risk of an opioid overdose or have household members, such as children, who may be at risk for accidental ingestion or opioid overdose [100]. (See "Opioid use disorder: Epidemiology, clinical features, health consequences, screening, and assessment".)
A patient counseling guide has been developed to assist clinicians in conducting important conversations about safety in patients for whom an opioid analgesic is prescribed. These preventive measures may be applicable to certain patients receiving chronic opioids for malignant pain.
Opioid dose reduction — Clinicians may perceive that patients receiving opioids for chronic cancer pain are never able to reduce the dose without risk of a pain flare or opioid withdrawal. Although it is true that those with progressive disease, complications of the cancer, or serious comorbidities may rarely do so, patients commonly present with more stable disease, or other scenarios that warrant consideration of opioid dose reduction. Circumstances that may warrant this consideration include [4]:
●Patient rarely or never needs breakthrough analgesic
●Completion/resolution of an acute pain event
●Improvement of pain control through use of non-opioid pain management strategies (eg, celiac plexus neurolysis, adjuvant analgesic) (see "Interventional therapies for chronic pain" and "Cancer pain management: Role of adjuvant analgesics (coanalgesics)")
●Well-controlled pain in the setting of stable or responding disease
●If the patient is experiencing unmanageable adverse effects and pain is <3 (mild), consider downward dose titration and reevaluate
Although there is large variation in the propensity for signs of opioid withdrawal associated with opioid dose reduction, and variation in the specific manifestations, patients generally reduce the dose without substantial adverse effects. A reduction of 10 to 20 percent of the total daily dose usually is tolerated. Should pain increase or signs of withdrawal appear, such as anxiety, insomnia, jitteriness, or diarrhea, the opioid dose can be increased and a smaller dose reduction implemented after the patient stabilizes.
DRIVING SAFETY — Cognitive and psychomotor adverse effects of opioids could potentially impair the ability to drive or work safely. Opioids can slow reaction time, cause drowsiness, or cloud judgment, particularly when they are first started, or when doses are increased [101]. For cancer patients with chronic pain, these effects could be further compounded as a result of the disease state itself, and the concomitant cancer treatment.
There are no large trials examining the risk of driving while on opioids. Most epidemiologic studies and reviews suggest that motor vehicle accidents and fatalities, and citations for impaired driving, are not disproportionally increased among patients receiving chronic stable doses of opioids (defined as no dose changes for at least one week [102]):
●A systematic review of three studies that reported data on driving simulation, on-the-road driving tasks, or driving outcomes in patients with chronic nonmalignant pain taking regular therapeutic opioid agonists [101,103,104] concluded that there was no significant impact of regular opioid intake on driving-related psychomotor skills [105].
●In another study, which videotaped patients while actually driving, those on chronic opioid therapy versus healthy controls showed neither a difference in driving errors in community or obstacle course driving, nor in tests of attention [106].
●In the only study limited to cancer patients receiving chronic morphine therapy, who completed a series of psychological and neurological tests to assess driving ability and were compared with cancer patients not on opioids, there was no significant difference in driving ability, although patients on morphine tended to perform less well [107]. The authors concluded that cancer patients receiving long-term therapy with stable doses of morphine do not have psychomotor effects of a kind that would be clearly hazardous in traffic.
On the other hand, a pair-matched study derived from the Fatality Analysis Reporting System for 36,642 drivers involved in 18,321 fatal two-vehicle crashes on United States public roads between January 1993 and December 2016 concluded that driver use of prescription opioids was associated with a twofold higher risk of initiating a crash compared with drivers who tested negative (odds ratio 2.18, 95% CI 1.91-2.48), and the effect was independent of alcohol use.
No studies have evaluated the effects of chronic opioid therapy on work safety.
These data, while limited, support the view that clinicians should carefully assess patients who intend to drive. Unfortunately, clinicians often appear to neglect this assessment and fail to educate patients and caregivers adequately [108].
For patients initiating opioid therapy for chronic pain or changing doses, most experts agree that driving or operating heavy machinery is unsafe and should probably be avoided until a stable dose, with stable clinical effects and no experience of cognitive change, has been reached [102,109,110]. Patients who have been on a stable dose of an opioid for a period that is at least a week beyond the estimated time that a steady state will be attained (eg, 9 to 10 days after starting or changing the dose of an oral extended-release formulation of morphine, oxycodone, or other drugs) and who have had stable effects, including no adverse cognitive changes, can drive.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Palliative care" and "Society guideline links: Neuropathic pain" and "Society guideline links: Cancer pain".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Managing pain when you have cancer (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Pain management within the context of palliative care
•Pain is a highly prevalent symptom in patients with cancer. Adequate pain relief can be achieved in more than 70 percent of patients when well-accepted treatment guidelines for cancer pain are followed. However, undertreatment may affect over 40 percent of patients with cancer-related pain. (See 'The problem of undertreatment' above.)
•Among individuals with cancer, pain is best considered as a domain within the broader context of palliative care, an interdisciplinary therapeutic approach that focuses on the comprehensive management of the physical, psychological, social, and spiritual needs of patients with serious or life-threatening diseases and their caregivers. (See 'Pain management within the context of palliative care' above.)
Most recommended therapies for cancer pain are within the scope of both specialty and primary care medical practice, and the adequate treatment of cancer pain should be viewed as a best practice for all medical disciplines involved in the care of this population. When the clinical issues are complex, particularly when pain is difficult to control or accompanied by other concerns, referral to a palliative care specialist may be appropriate.
●General principles of pain management – An effective strategy for cancer pain management is predicated on the following broad principles (see 'General principles of pain management' above):
•The goal of the initial assessment is to characterize key elements of the pain, including the presence of a pain syndrome, if one can be defined, inferred pathophysiology and etiology of the pain, and disease extent as well as prior antineoplastic treatment. Reassessment is indicated whenever a change occurs. (See "Assessment of cancer pain" and "Overview of cancer pain syndromes".)
•Clinicians should always consider the possibility of disease-modifying antineoplastic therapy or other interventions directed against the etiology of the pain.
•A stepwise and systematic approach to pain control should consider selection of appropriate drugs and prescribing techniques that can optimize their pharmacological outcomes (table 1). (See "Cancer pain management with opioids: Optimizing analgesia".)
●Risk assessment and management
•The ability to assess and manage the risk of abuse, addiction, and diversion is one of the foundations to safe and effective opioid prescribing. The importance of risk management during the treatment of cancer pain is underscored the prevalence of opioid use disorder in populations with cancer-related pain, estimated to be approximately 8 percent. (See 'Risk assessment and management for patients receiving opioids' above.)
When the risk of aberrant drug-related behavior is assessed as low (as it is in most patients with cancer pain), prescribing of an opioid can proceed with simple and straightforward strategies for adherence monitoring and controlling drug use. Patients who are considered to be at relatively higher risk for aberrant drug-related behavior should have additional "control measures" incorporated into therapy (table 4). (See 'Risk management' above.)
•We recommend all patients regularly taking opioids for cancer-related pain maintain a supply of naloxone for opioid reversal. (See 'Preventing lethal overdose' above.)
●Driving safety – Clinicians should counsel all patients on chronic opioid therapy about the potential for transient or lasting cognitive impairment that may affect driving or work safety. Patients who have been on a stable dose of opioids for at least one week who feel no cognitive changes can drive. However, for patients initiating opioid therapy or changing doses, driving or operating heavy machinery is unsafe and should probably be avoided until a stable dose has been reached. (See 'Driving safety' above.)
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