Opioid Crisis Spurs New Strategies for Cancer Pain

William Dale, MD, PhD

It wasn't too many years ago that the primary concerns related to pain management for patients with cancer revolved around whether they were getting adequate relief. Now, with the United States in the throes of an opioid epidemic, the use of these powerful and addictive pain relievers for patients with cancer is coming under unprecedented scrutiny.

Major cancer centers are examining their current protocols to develop new ways to manage pain with shorter courses of opioids— or, if appropriate, with nonopioid approaches. Oncologists are increasingly being advised to assess patients for their risk of developing opioid dependence and monitor them for signs of abuse.

As more patients achieve long-term survivorship, the need for better management of pain medication will become more pressing, Alison Wakoff Loren, MD, MSCE, noted recently in a perspective for the New England Journal of Medicine.¹

Dimensions of the Epidemic

“Oncologists are accustomed to giving opioids, but we must also be comfortable taking them away and sometimes giving them in limited doses or not at all,” wrote Loren, an associate professor of medicine in the Division of Hematology/Oncology at the Hospital of the University of Pennsylvania in Philadelphia. “We need to be aware of risk factors for substance use disorders and tools for preventing and addressing them… Although many cancer survivors live with chronic health issues caused by their treatment, opioid addiction should not be one of them.”The emphasis on opioid prescribing practices in cancer care comes amid a grim litany of statistics about the nation’s drug abuse problems. Prescription opioids have been identified as significant contributors to the overdose epidemic. The Centers for Disease Control and Prevention (CDC) reports that more than 35% of all US opioid overdose deaths in 2017 involved a prescription.²

In 2018, JAMA Network Open published a serial cross-sectional study that found that the percentage of deaths in the United States attributed to opioids rose 292% between 2001 and 2016.² That increase, from 0.4% (1 in 255) to 1.5% (1 in 65), represents 1.68 million years of life lost. During the same period, the rate of US opioid-related deaths increased from 3.3 to 13.1 deaths per 100,000.³

The age group bearing the highest burden was adults aged 25 to 34 years; in this age group, 1 in 5 deaths in the United States is now opioid related. However, adults aged 55 to 64 years, the most likely age group to be coping with cancer, experienced the largest relative increase in the proportion of deaths attributable to opioods, with an increase of 754%, from 0.2% to 1.7%.³

But what about opioid-related deaths and addiction among patients with cancer? Several medicines commonly used to treat cancer pain, including fentanyl, hydrocodone, methadone, morphine, and oxycodone, were among the drugs most frequently involved in fatal overdoses in the United States from 2011 to 2016, according to the CDC’s National Center for Health Statistics.⁴

However, there are few statistics on the incidence and impact of opioid abuse among patients with cancer. Findings from a study presented at the American Society of Clinical Oncology (ASCO) 2018 Quality Care Symposium showed that patients with cancer were less likely to die of an opioid overdose than the general population. Nevertheless, the incidence of these deaths rose over a 10-year period.⁵

Meanwhile, results from other studies indicate that many patients with cancer face a high risk of misusing prescription opioids. Investigators at The University of Texas MD Anderson Cancer Center in Houston found that 29% of 522 patients whose charts they reviewed were at high risk for opioid misuse. Patients with scores ≥4 on the Screener and Opioid Assessment for Patients with Pain-Short Form were more likely to be younger than 55 years, have a higher morphine-equivalent daily dose, and report more feelings of pain, depression, and anxiety.⁶

The CDC’s Response

At the University of Michigan in Ann Arbor, investigators examined patterns of persistent opioid use among patients with cancer who had undergone curative-intent surgery from 2010 to 2014. The review consisted of insurance claims from 68,463 patients who had surgery for melanoma, breast, colorectal, lung, esophageal, and hepato-pancreato-biliary/gastric cancer. The findings showed that the risk of new persistent opioid use among opioid-naïve patients was 10.4% (95% CI, 10.1%-10.7%). A year after their surgeries, these patients were filling prescriptions with daily doses equivalent to 6 tablets per day of 5-mg hydrocodone.⁷In response to the broad public health crisis, the CDC sought to take control of the situation in 2016 by issuing the CDC Guideline for Prescribing Opioids for Chronic Pain.⁸ These voluntary guidelines apply to the prescribing of opioid pain medication for patients 18 and older in primary care settings. Although they specifically exclude active cancer treatment, palliative care, and end-of-life care, the CDC guidelines have nonetheless had a significant effect on both oncologists and their patients.

Table. NCCN Guidelines for Managing Cancer Pain ≥4 in Opioid-Tolerant Patients¹¹

Key features of the CDC guidelines include reduced dosage recommendations compared with previous versions. Additionally, earlier guidelines stratified risk, urging extra safety precautions for patients deemed to be at high risk of opioid-related difficulties. The new guidelines note that “opioids pose risk to all patients, and currently available tools cannot rule out risk for opioid use disorder or other serious harm” and are more specific with preferred strategies for both monitoring and discontinuing opioids. The National Conference of State Legislatures reports that, in response to the CDC guidelines, 33 states had enacted legislation that imposed limits or requirements related to opioid prescribing by October 2018.⁹ The most common legislative action is to limit new opioid prescriptions to a set number of days, most often 7 days. Some states also set dosage limits in morphine milligram equivalents or require compliance with state prescription drug monitoring programs. States generally exempt treatment for cancer and chronic pain and palliative care from prescription limits, although the increased administrative requirements apply to all prescribers.

Insurers have also responded to the CDC guidelines. For example, America’s Health Insurance Plans launched its Safe, Transparent Opioid Prescribing Initiative in 2017. A centerpiece of the benchmarking project is collecting data from more than 40 health plans “with the hope that it will encourage widespread adoption of the Centers for Disease Control and Prevention Guideline for Prescribing Opioids for Chronic Pain,” as the trade association’s president, Matt Eyles, wrote on the group’s website.¹⁰

Guidelines for the Oncology Community

Many insurers now take an active role in directing physicians’ opioid-prescribing practices, whether by increasing documentation requirements or by requiring trials of nonopioid medications before authorizing opioids. It’s also become common for insurers and health systems to track institutional and individual prescriber compliance with the CDC guidelines.Since these large-scale policy directives from governmental bodies, professional societies, payers, and health systems will undoubtedly continue, oncologists will have to think creatively to manage their patients’ pain effectively within today’s challenging atmosphere, experts say.

The National Comprehensive Cancer Network has incorporated recommendations for managing the pain of patients who have become tolerant to opioids into its supportive care pain guidelines for adult patients. The guidelines suggest dose reductions followed by additional assessment and specialist consultation for those who continue to report moderate to severe pain (Table).¹¹

ASCO guidelines advise cancer care providers to screen patients for pain levels at every visit, and for those who report chronic pain (lasting ≥3 months), prescribe systemic nonopioid analgesics and adjuvant analgesics. Opioids may be considered for those who do not respond to more conservative choices. The guidelines also stress the need for clinicians to learn about precautions and strategies to help their patients avoid opioid abuse.¹²

Cancer centers also are experimenting with pain management practices in an effort to decrease opioid use. For example, gynecologic surgeons at Roswell Park Comprehensive Cancer Center in Buffalo, New York, tested a protocol to restrict the prescribing of opioids. Patients who underwent minimally invasive/ ambulatory procedures and had no history of chronic pain received a 7-day supply of prescription-strength ibuprofen or acetaminophen. Patients who required 5 or more pills/doses of opioids or who had a history of chronic pain requiring opioids received a 3-day prescription, as opposed to the state-allowed 7-day prescription.¹³

A Larger Role for Pharmacists

The protocol resulted in an 89% reduction in the number of opioid tablets dispensed at discharge and a high rate of patient satisfaction, according to study findings presented at the 2018 Society of Gynecologic Oncology Annual Meeting.¹³Collaborative approaches also are recommended. Pharmacists have always been valuable partners to oncologists in optimizing patients’ medications for their pharmacological expertise; now, their strategic and supply-chain knowledge can add even more value.

William Dale, MD, PhD, the Arthur M. Coppola Family Chair in Supportive Care Medicine at City of Hope Cancer Center in Duarte, California increasingly relies on his pharmacy colleagues for strategic support in managing patients’ access to opioids.

“When we first encountered the more restrictive policies here, we began weekly meetings with pharmacy about which opioids were available so that, at least on the inpatient side, we didn’t suddenly run out of medicines,” he said in an interview with OncologyLive^®. “Now we seem to be hitting a new normal. Our meeting this week lasted only 15 minutes to touch on naloxone availability, the CURES database, and how to ensure we meet the new rules on both.” [CURES is the Controlled Substance Utilization Review and Evaluation System that California maintains.]

Managing patients’ pain on an outpatient basis has its own challenges, of course. “At City of Hope, because we know what our own pharmacy has, we will increasingly ask people to fill their opioid prescriptions in our pharmacy,” Dale said.

Palliative Care Collaborations

When patients don’t live nearby, Dale either calls the patient’s pharmacy to learn the available drug options there or he will suggest that the patient obtain the preferred drug at a specific pharmacy. “I used to assume that if I came up with a medically appropriate regimen, then patients would be able to get those medicines,” he said. “These days it’s the reverse. I have to develop an appropriate, effective pain regimen based on what’s available.”The whole-patient perspective that palliative care specialists bring can also be invaluable to oncologists. As an oncologist whose primary appointment is in palliative care at MD Anderson, David Hui, MD, MSc, knows that each discipline has its strengths. “As palliative care physicians, opioids are our most-used drugs, so we become very comfortable using them to achieve optimal pain control while maximizing patient function, quality of life, and also minimizing adverse effects and abuse,” he said in an interview. “Many oncologists do this very well, but the entire practice of palliative care has always been based on thorough assessment and monitoring. Knowing when to get help from a palliative care specialist is important.”

At Massachusetts General Hospital, medical oncologist Tara E. Soumerai, MD, has done just that. “With all of the prescribing challenges created by the opioid epidemic, we are leaning heavily on our teambased approach more than ever,” she says. “As a hospitalist, I often have to manage pain crises in patients, yet opioid shortages and restrictions affect us as much as anyone. Some available opioids are not as familiar to me or I’m not as experienced in prescribing them, so I find I’m calling my palliative care colleagues more often and sooner in the admission.”

It may also be helpful for oncologists to remember that the CDC guidelines, which specifically favor fast-acting opioids for shortterm use, were not written to address the treatment and management of cancer-related pain, says Fumiko Chino, MD, a radiation oncologist at Duke University and lead author of the study into opioid overdoses.⁵ “Our patients have long-term needs. Keeping patients on shortacting pain medications that wear off in a few hours, [as the guidelines suggest], is both less effective and less safe than transitioning them over time to a longer-acting agent so that pain levels don’t yo-yo and patients can continue to function,” she said. “Palliative care colleagues are experts at striking that balance.”

Nonopioid Alternatives

Hui welcomes the increased referrals. “Early referral is a win-win situation for the patient, who gets better, more comprehensive management as a result,” he said. “We enable the oncologist to focus on other aspects of cancer care while knowing their patients’ symptoms will be well controlled. The palliative team will have the satisfaction of knowing they’re able to optimize patients’ care.”As the restrictions on opioids continue to tighten, one of the best ways to continue to provide good pain management regimens is to keep current on emerging nonopioid alternatives. For example, gabapentin and pregabalin have recently come to prominence as nonopioid therapies that can work either alone or in combination with opioids to treat neuropathic cancer pain.

But Dale, who was trained as a geriatrician, suggests caution. “Since the gabapentins affect the central nervous system, these drugs can have cognitive effects and increase fall risks for older patients,” he says. “Their therapeutic window is pretty narrow and can be difficult to hit without overdosing. But even though I’m not a fan, I find myself using them more often.”

Dale is also wary of using the so-called muscle relaxants, such as baclofen, to treat cancer pain. “These drugs work in a generalized manner and effectively make the entire body weaker, at least in older people,” he says. “They’re on the Beers list [of drugs that should not be given to older patients] because they affect alertness and balance.”

Antidepressants have also entered the cancer pain management arsenal as effective nonopioid therapies effective against neuropathic pain. Duloxetine (Cymbalta) is used to combat chemotherapy-induced peripheral neuropathy, while venlafaxine (Effexor) can help reduce hot flashes in patients with breast cancer.

Older tricyclic antidepressants, such as amitriptyline, desipramine, and nortriptyline, can also be used to treat neuropathic pain. Dale suggests that colleagues consult the American Geriatrics Society Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults before starting elderly patients on antidepressant therapy.¹⁴

Manage Patient Expectations

Emphasizing appropriate nonmedical modalities like massage, meditation, physical therapy, or applied heat and cold as part of an effective pain management regimen can often allow for lower opioid dosing, as can topical formulations like lidocaine patches or rinses.Patient education has always been a vital component of oncology practice, but the opioid crisis may be changing the nuances of what patients fear and the kinds of reassurance and information they need from their medical team.

Many oncologists report that the opioid epidemic has left some patients afraid or even unwilling to take opioids. “They have heard these rallying cries in the news, and it makes some of our most vulnerable patients with metastatic disease resistant to even trying some of these medications. They try to get by with just acetaminophen or ibuprofen,” said Chino, adding that many patients have shared heartbreaking stories about opioid-related fatalities in their own families. “I often have to work hard to convince patients who are in tremendous pain to take a low-dose opioid to enable them to complete treatment.” Seeing patients suffer needlessly is its own kind of heartbreak, she said.

For Dale, helping patients and families move beyond the old paradigm of 0 pain on a 0 to 10 pain scale has been critical. “That is no longer a realistic goal, if it ever was. I tell patients I want their pain to be as little as possible while still allowing them to be awake, interactive, and able to do the things that are important to them,” he said. “If that means tolerating a little more pain, most people are happier with that trade-off, and it’s safer for them.”

References

1. Loren AW. Harder to treat than Leukemia — opioid use disorder in survivors of cancer. N Engl J Med. 2018;379(26):2485-2487. doi: 10.1056/NEJMp1812850.
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9. National Conference of State Legislatures. Prescribing policies: states confront opioid overdose epidemic. NCSL website. ncsl.org/research/health/prescribing-policies-states-confront-opioid-overdose-epidemic.aspx. Published April 5, 2018. Accessed December 17, 2018.
10. Eyles M. Insurers are well-positioned to address opioid epidemic. America’s Health Insurance Plans website. ahip.org/insurers-are-well-positioned-to-address-opioid-epidemic/. Published October 25, 2018. Accessed December 17, 2018.
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13. Mark JE, Phoenix D, Gutierrez CA, et al. Tackling the opioid crisis: implementation of an ultra-restrictive opioid prescription protocol in patients undergoing major gynecologic surgery radically decreased dispensed opioid without reducing pain control. Presented at: SGO Annual Meeting; March 24-27, 2018; New Orleans, LA. Abstract 7. doi: 10.1016/j.ygyno.2018.04.018.
14. American Geriatrics Society updated Beers criteria. GeriatricsCareOnline.org website. geriatricscareonline.org/ProductAbstract/american-geriatrics-society-updated-beers-criteria-for-potentially-inappropriate-medication-use-in-older-adults/CL001. Published 2015. Accessed January 9, 2019.