Approaches to Opioid Prescribing in Cancer Survivors: Lessons Learned from the General Literature

Lay Summary:

Guidance on how to approach opioid decisions for people beyond active cancer treatment is lacking; this editorial discusses strategies from the general literature that can be thoughtfully tailored to cancer survivors to provide patient-centered pain and opioid care.

Precis:

Cancer survivors are a heterogeneous population with high rates of chronic pain and prescription opioid receipt. Nuanced guidance on how to approach opioid decisions for people beyond active cancer treatment is lacking; this editorial discusses strategies from the general literature to facilitate safe opioid prescribing decisions in cancer survivors.

We thank Salz et al. for their valuable contribution to the literature on the important topic of long-term opioid therapy (LTOT)in older adult cancer survivors. This retrospective study using Surveillance, Epidemiology, and End Results (SEER)-Medicare data describes opioid prescribing to 82,471 opioid-naïve cancer survivors (defined by researchers as individuals alive 15 months after diagnosis and treatment) of stage I-III breast, colorectal, lung, and head and neck cancer. The authors reported that 3,628 (4.4%) participants received LTOT during the first year after treatment. The authors acknowledge this is likely an underestimate due to the strict study inclusion criteria. Several important characteristics of those who received LTOT were noted: 8% received high-dose opioids (> 90 mg of oral morphine equivalents), 25% were co-prescribed benzodiazepines, and 24% were co-prescribed gabapentenoids. The characteristics observed are critically important because they represent high-risk opioid prescribing features, including elevated risk for opioid-related harms and unintended opioid overdose.¹

This study is part of a growing body of literature describing opioid continuation for more than a year beyond initial cancer treatment.² The majority of cancer survivors receive opioids during cancer treatment, and at least a third will continue to experience chronic pain even after completing cancer treatment.³ Salz et al.’s work and other relevant literature demonstrate LTOT and substance use prevalence rates in cancer survivors are often higher than the mean national prevalence.^2,4 Opioids are an important aspect of pain management during active treatment and in advanced cancer, but the role of opioids for those who have completed curative treatment is less clear.

Indeed, given the well-established risks of LTOT for chronic pain in the general population, we argue that LTOT in cancer survivors represents the development of a new and potentially serious health challenge in this group. In people without cancer, LTOT is associated with numerous harms, including decreased function, inadequate pain control, inability to return to work, falls, depression, fatigue, osteoporosis, sexual dysfunction, and immune system effects—as Salz et al. emphasize conditions to which cancer survivors are already predisposed.^5,6 LTOT can also lead to opioid misuse, opioid use disorder (OUD), and overdose. In the general population, the rate of opioid misuse is approximately 25%, and the development of OUD occurs in 10% of people receiving LTOT.⁷ Table 1. provides definitions of the commonly used terms pertaining to chronic pain, LTOT, and opioid misuse/ use disorders.

Table 1:

Common Terms and Definitions

Common Terms	Definitions	Additional relevant information
Chronic pain	Chronic pain is most commonly defined as pain that persists or recurs > 3 months. Chronic pain is often considered a chronic disease that is influenced by biopsychosocial factors.1	Common chronic pain syndromes in cancer survivors include CIPN, hormone-therapy-related pain syndromes, radiation-related pain syndromes, lymphedema, graft-versus-host disease, post-surgical pain such as phantom pain, post-mastectomy pain, post-thoracotomy pain.2
Long-term opioid therapy (LTOT)	Most commonly defined as opioid use for > 3-months.3	Operationalizing the definition of LTOT varies in the literature and does not necessarily always measure consistent use. Studies in cancer care also refer to opioid use > 3 month after completion of treatment as “persistent opioid use” 4
Universal Precautions	A standardized approach to the assessment and management of chronic pain and opioid therapy applied to all patients.5,6	Examples include diagnosing pain etiology, obtaining a substance use history, assessing for opioid misuse behaviors (including checking the PDMP and urine drug screening), discussing and documenting the risks and benefits of opioid therapy, and assessing opioid benefits and harms frequently.7
Opioid Misuse	A collection of behaviors involving the use of opioids in ways other than prescribed that is often associated with increased risk for opioid harms.8	Manifestation of opioid misuse includes running out of opioids early, aggressive behavior about opioids, and using other substance use from non-medical sources. 9 Clinicians should use a differential diagnosis for opioid misuse behaviors such as exploring a patient’s understanding of opioid regimen, assessing for worsening of underlying pain syndrome, or using the DSM criteria to assess for OUD if a concerning pattern emerges. Other terms for opioid misuse in the literature include aberrant use, concerning opioid behaviors, or risky opioid use.
Complex Persistent Opioid Dependence	Although there is no widely accepted definition, the clinical manifestations include insufficient pain control, worsening function, psychiatric instability, and opioid misuse that does not meet the clinical criteria of OUD. 10	Research on complex persistent opioid dependence is emerging. There is debate as to whether this is a mild form of OUD or an alternative syndrome that deserves a unique diagnosis and treatment strategy.11 Symptoms associated with complex persistent opioid dependence are frequently exacerbated during attempts to taper opioids. 10
Opioid Use Disorder (OUD)	A problematic pattern over at least 12 months of opioid use meeting at least 2 of 11 DSM specific criteria, including loss of control over and continued use despite harms leading to significant distress.12 OUD ranges from mild, moderate, to severe.	In patients prescribed opioids, manifestations of OUD may include taking more opioids than prescribed (loss of control), ongoing use despite strained relationships with family and healthcare team (use despite consequences), and self-escalation of opioids (compulsive use). No single behavior indicates an OUD diagnosis, but rather it is a collection and pattern of behaviors over time. Tolerance and withdrawal do not contribute to an OUD diagnosis in people prescribed opioids.9,12

Despite a rich and growing body of literature on risks and management of LTOT for chronic pain, little literature focuses on cancer survivors. In fact, individuals with cancer are typically systematically excluded from studies examining the safety, efficacy, and practice of opioid prescribing for chronic pain.⁸ Moreover, cancer survivors are a diverse population, including people with average life expectancies and others with limited prognoses. Survivorship can also involve fluid movement between various disease states (e.g., cure, prolonged periods of disease stability, cancer recurrence, or development of a second malignancy).⁹ Therefore, this situation poses unique challenges for clinicians, who must consider managing the complexities of a broad category of people with potential cancer and non-cancer chronic pain syndromes, varying prognoses, and associated comorbidities.

Existing oncology guidelines such as those from the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network address chronic pain management and opioid use in cancer survivors.^10,11 Their recommendations vary according to population (i.e., differentiation of patients undergoing active cancer treatment between those who have completed cancer treatment) and practice setting (oncology, survivorship care, or palliative care),⁸ but regard opioids as an aspect of cancer pain treatment. However, nuanced, evidence-based recommendations on how to best approach opioid prescribing decision-making is lacking.¹² For example, assessing for risk of opioid harms at the onset of treatment is emphasized in cancer and non-cancer guidelines, but more recent evidence suggests available screening tools to stratify individual risks for opioid misuse or use disorder have poor diagnostic accuracy identifying high or low-risk patients, and no signs, symptoms, or tool can identify people at low-risk for opioid harms.¹³ Also state-based laws on opioid prescribing vary and do not clearly exempt those beyond active diagnosis and treatment, potentially limiting dose and opioid duration in cancer survivors residing in some states.¹⁴ There are no guidelines on managing OUD, maximizing opioid safety, and establishing criteria for referring to specialty pain or addiction care in cancer survivors. ^10,12 Additionally, how cancer stage, treatment, prognosis, and practice setting influence these challenging decisions is not incorporated into opioid recommendations.^10,12 The amalgamation of the outlined issues reflect how truly complex opioid decisions are in cancer survivors.⁸

Unsurprisingly, palliative care, oncology, and primary care clinicians report having insufficient knowledge and lack of confidence in managing chronic pain and LTOT in cancer survivors.^15–17 Consequently, up to 50% of cancer survivors report not discussing, getting advice, or receiving desired help for pain and psychosocial distress.¹⁸ It will take time to fill the large literature gap on how to best tailor chronic pain and opioid decision-making to cancer survivors who may be on active treatment (including chronic treatment) or finished disease-directed therapy or receiving palliative care. In the meantime, we suggest drawing on evidence-based approaches from the non-cancer literature. Here, we present a few examples of how this can be done.

Employ risk mitigation strategies

Risk mitigation strategies are a collection of behaviors and interventions intended to optimize the safety of opioids as much as possible. As Salz et al. point out, it is unclear who is ideally suited to managing opioids and pain needs in cancer survivors. But the opioid prescriber, at a minimum, should be responsible for several key universally recommended opioid risk mitigation strategies. First, completing an opioid treatment agreement that reviews expectations and informed consent about potential opioid risks, benefits, and alternatives. Second, checking the state prescription drug monitoring program (PDMP) database to ensure opioid or other (e.g., benzodiazepine) prescriptions have not been obtained from other clinicians. In cancer care, mandatory accessing PDMPs before opioid prescribing is associated with a decrease in opioid prescribing, but it is unclear if declining opioid prescribing is the right metric without more information on patient-level data. ¹⁹ Third, urine drug testing should be done before starting opioid therapy and at least annually to assess adherence and presence of unanticipated substances.²⁰ Finally, naloxone provision is recommended with LTOT, especially with high-dose opioids. ²⁰ The Centers for Disease Control and Prevention recommend consideration of naloxone to patients receiving greater than or equal to 50 morphine milligram equivalence per day, co-prescribing of other sedating medications such as benzodiazepines, or in patients with comorbidities that may place individuals at high risk for unintended overdose (i.e. mood disorders, post-traumatic stress disorder, and history of substance use disorder).^20–22 Universal precautions are approaches provided to all patients prescribed opioids that reduce the risk of harm and involve minimal risk to the patient when done accurately (in the case of urine drug testing) and compassionately.

To help clinicians incorporate risk mitigation strategies in their practice, we recommend the web-based platform Transforming Opioid Prescribing in Primary Care (mytopcare.org), which provides an array of resources on informed consent, urine drug testing, and assessing the benefits and harms of opioid therapies.²³ We advocate for using this resource as a starting point but acknowledge it is not specific to cancer survivors.

Use evidence-based adjuvant therapies that consider comorbidities

Salz et al. highlight the use of adjuvant treatments to manage chronic pain in cancer survivors. While we agree that non-opioid pharmacologic therapies are integral to chronic pain management and highlighted in national guidelines, we also stress the importance of considering which treatments are evidence-based. The ASCO guidelines acknowledge that adjuvant analgesics’ long-term efficacy and safety have not been established in cancer survivors.¹⁰ Medications for pain and symptom management are often prescribed off-label, especially in situations when prognoses are short. However, the potential benefits of this approach should be weighed against its potential harms, particularly in the case of cancer survivors who may have longer prognoses and be medically complex.⁸

In this study, gabapentinoids were used by nearly a quarter of those on LTOT. Gabapentin is known to increase the risks associated with LTOT; extensive off-label prescribing of gabapentin has been well-documented.^24,25 There is evidence on the effectiveness of gabapentin for post-surgical pain, but improvements are limited to early in the postoperative period, not for chronic post-surgical pain syndromes, such as post-mastectomy pain.²⁶ Moreover, the use of gabapentin is not recommended for chemotherapy-induced peripheral neuropathy (CIPN), one of the most common pain syndromes in cancer survivors.²⁷ CIPN can be associated with motor symptoms, including issues with balance and falls that may be worsened by the use of polypharmacy, especially in older adults.^27–29 So, while Salz et al. equate non-opioid pharmacologic therapies with enhanced safety and efficacy, this may be overstated and is contingent upon patient-level and pain-related factors.

Salz et al. categorize antidepressants as adjuvant analgesics because these agents are commonly used to treat neuropathic pain syndrome in cancer survivors. Antidepressants were used by 18% of the cohort, although it is unclear if the indication was pain or depression. Unfortunately, evidence suggests the effectiveness of antidepressants is less for cancer pain syndromes than non-cancer pain syndromes, with efficacy dependent on the underlying pain mechanism.³⁰ For example, CIPN causes pain through a unique mechanism of neuronal damage not seen in other peripheral neuropathic pain syndromes like diabetic peripheral neuropathy. ²⁷ This alternative mechanism is thought to explain why existing evidence for duloxetine and tricyclic antidepressants do not demonstrate effectiveness.²⁷ A better understanding of the phenotypes of chronic pain syndromes and analgesic responsiveness is needed to appropriate tailor adjuvant treatments to cancer survivors.³¹

Greater evidence for non-pharmacologic and lower-risk treatments for chronic cancer pain treatments are needed. Consistent with the general population of cancer survivors, one-third of the study sample had greater than two non-cancer comorbidities.³² The presence of comorbidities makes polypharmacy and off-label pharmacologic treatments risky- whereas non-pharmacologic treatment may be preferred.³³ For example, acupuncture is a safe and effective treatment for CIPN, but its use is limited and inequitable because it is not widely covered by insurance.^10,27,34 Additionally, physical therapy or exercise-based interventions like yoga, are promising for many cancer pain syndromes but may not always be adapted or available to cancer survivors.^35–37 More work is needed to understand the psychosocial aspects of chronic pain to promote greater use of pain self-management techniques such as stress-based coping skills training that may improve pain and reduce polypharmacy.^33,38 Improving the provision of high-quality pain care for cancer survivors is also contingent upon a new treatment paradigm that expands equitable access to safe and effective multimodal treatments that comprehensively address the biopsychosocial factors that influence chronic cancer pain.⁸

Salz. et al. observed anxiety and depression in 58% of cancer survivors on LTOT, highlighting the relationship between LTOT and mood symptoms. ³⁹ Screening for mood symptoms using a validated tool such as the Patient Health Questionnaire (PHQ) before initiation of opioids and continual assessment of mood symptoms and cancer distress is critical during cancer survivorship.^40–42 Depression doubles the risk of transitioning from short-term to LTOT in various non-cancer pain syndromes.^43,44 Moreover, new-onset depression or worsening depression can occur with LTOT, especially with prolonged duration or rapid dose escalation.^45,46 Depression is also associated with greater opioid misuse, including using opioids to treat insomnia or other non-pain symptoms.⁴⁰ Lowering the opioid dose or rotation to buprenorphine may be considered in individuals prescribed high-dose LTOT who also have concurrent or refractory mood symptoms.⁴³ Buprenorphine is a unique partial opioid agonist with a variety of potential uses in cancer survivors outlined in table 2. Because of buprenorphine’s activity on the kappa receptor in early trials, it appears to benefit mood symptoms while simultaneously being a safer option to address chronic pain.^39,47

Table 2.

Possible Considerations for Rotation to Buprenorphine^* in Cancer Survivors with Chronic Pain

• Facilitate patient-centered opioid tapering

• Complex persistent opioid dependence

• OUD

• Opioid Misuse Behaviors that increase the risk for opioid harms (i.e., other substance use)

• Adverse effects from LTOT such as endocrine dysfunction (low testosterone or sexual dysfunction), mood disorder, falls, protracted withdrawal, hyperalgesia

^*A DEA X waiver is only required to prescribe buprenorphine for OUD. Effective April 2020, the education requirement has been lifted to treat < 30 patients with buprenorphine, but a notice of intent to the Substance Abuse and Mental Health Service Administration (SAMHSA) must be completed before prescribing buprenorphine. The notice of intent can be completed at https://buprenorphine.samhsa.gov.

An X waiver is not required for pain or situations that do not meet criteria for OUD but obtaining an X waiver allows clinicians to use buprenorphine/naloxone off-label for pain, opioid misuse, opioid tapering, and complex persistent opioid dependence. Without an X waiver, clinicians may be limited to transdermal, intravenous, and buccal forms of buprenorphine-most often used for opioid naïve populations. The buprenorphine X waiver patient limits do not apply when the prescribing indication is pain.

Adopt a patient-centered approach to assessing the benefits and harms of LTOT

Another strategy used to minimize opioid harm is to assess the benefits and harms of LTOT regularly and, if the harms outweigh the benefits, consider a patient-centered taper. Patient-centered tapering prioritizes the unique needs of each patient and proceeds in a manner informed by the individual’s situation keeping patient safety at the forefront of decision-making. Importantly, opioid tapers should include supportive shared-decision making, and abruptly tapering or discontinuing opioid treatment is rarely indicated.⁴⁸ Clinicians should develop a therapeutic relationship with patients and communicate the tapering rationale, schedule, and symptoms that may be experienced during the tapering process.^10,49 Opioid tapering is an evolving area of research. It should be undertaken with caution in patients at risk for psychological decompensation but evidence suggests slow, flexible, and voluntary tapering can improved function, quality of life, mood, and pain management.^48,50–52 Unfortunately, sometimes, even when opioid tapering is individualized and accompanied by robust psychosocial support, it can be difficult for some patients to tolerate.^52,53 Buprenorphine can facilitate opioid tapers by minimizing hyperalgesia and promoting mood stability attributed to prolonged abstinence syndrome.⁵⁴ The use of buprenorphine to facilitate patient-centered opioid tapers is endorsed by the Health and Human Services Guidelines for Discontinuation of Long-Term Opioid Analgesics.⁵⁵

Make a diagnosis of OUD and offer treatment

Clinicians working in cancer care must be equipped to diagnose OUD and offer or directly facilitate treatment. OUD is defined as “a problematic pattern of opioid use leading to significant impairment or distress” over at least one year.⁵⁶ The 4Cs (cravings, control (loss of), consequence, and compulsive use) may be a helpful pneumonic for the diagnostic criteria of OUD that can range from mild, moderate, severe.⁵⁶ Notably, diagnosing OUD is not always straightforward. OUD-related behaviors may manifest differently in individuals receiving opioids from medical sources than those receiving them from non-medical (i.e., illicit) ones. ⁵⁷ It may be challenging to recognizing a problematic pattern of opioid use in cancer survivors who experience fragmented care and fluctuating symptoms, resulting in many opioid prescribers and dose adjustments.⁵⁸

In addition, there are common opioid challenges that do not meet the criteria for OUD but may increase opioid risks. One opioid challenge may include what some have termed “complex persistent opioid dependence,” a condition seen in people on LTOT characterized by poor pain control and declining function.⁵⁴ Another frequently encountered opioid challenge is opioid misuse behaviors, including occasional illicit substance use (e.g., cocaine), with some estimates reporting abnormal drug screens in 30-50% of cancer patients tested.⁵⁹

Although an accurate diagnosis of OUD is an important goal, clinically, we have observed our colleagues spending a lot of time trying to disentangle pain from addiction or decide whether opioid misuse or complex persistent dependence is severe enough to meet the diagnostic criteria for OUD.⁶⁰ We would argue that in these situations, rather than delaying action, rotation to buprenorphine is likely prudent. Buprenorphine has many advantages, such as high affinity for the opioid receptor and the ceiling effect for respiratory depression, making it safer and often better tolerated than a full opioid agonist.⁶¹ There is encouraging preliminary data supporting buprenorphine rotation in patients on LTOT who wish to reduce their opioid-related risk or who are experiencing poor pain control and declining function.⁶² Note that when prescribing buprenorphine for patients with OUD, an X-waiver added to a clinician’s DEA license is required. Effective April 27, 2021, the Health and Human Services released new Buprenorphine Practice Guidelines that allow DEA licensed clinicians to submit a notice of intent to apply for an X-waiver to treat up to 30 patients with OUD without completing the additional educational training or attesting to the ability to refer for counseling.⁶³ Being able to prescribe buprenorphine and becoming familiar with the diagnosis and treatment of OUD and high-risk opioid misuse in cancer survivors is an important call to action for oncology and palliative care interdisciplinary teams.

In summary, chronic pain and LTOT are common challenges faced by cancer survivors. Table 3. Highlights the critical research gaps that warrant future attention to help guide pain and opioid decisions in the cancer survivor population, but the general literature can provide guidance for patients who need our help managing these challenges now.

Table 3.

Research Gaps in Chronic Pain and Opioid Management in Patients with Cancer

• Understand the unique biopsychosocial factors that drive the chronic pain experience in cancer survivors.

• Investigate how a patient’s cancer trajectory (e.g., treatment plans and prognosis) should impact opioid prescribing decisions.

• Explore the role of buprenorphine for individuals with opioid misuse/OUD and concurrent cancer pain.

• Determine how and when to consider opioid tapering in cancer care.

• Develop optimal approaches to diagnosing and treating comorbid pain and OUD in cancer care.

• Expand evidence on non-pharmacologic treatments that address psychosocial aspects of chronic pain in survivorship.

• Minimize fragmented care by developing approaches to providing integrated opioid and pain care to cancer survivors.