In the wake of the opioid crisis in the United States, patients with cancer pain are often undeservedly confronted with rigid barriers to receiving the opioids they need. To compound this problem, the research around opioids in cancer pain has been limited—placebo-controlled trials are lacking, lessons from certain groups have been haphazardly applied to broader populations, and acute and chronic pain have been wrongly treated as the same entity—all factors that add to a general discomfort around prescribing these drugs for patients who legitimately need them.

Mellar Davis, MD

Declan Walsh, MD

At the 2019 Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) Annual Meeting in San Francisco,¹ Mellar Davis, MD, and Declan Walsh, MD, discussed the current challenges to opioid prescribing in the cancer setting.

What Is the Evidence?

Although opioids are the analgesic of choice for moderate to severe cancer pain, the evidence from trials is associated with a high degree of uncertainty, meaning future trials are very likely to alter conclusions, according to Dr. Davis, an oncologist and palliative care specialist at Geisinger Medical Center in Danville, Pennsylvania.

Few placebo-controlled trials have focused on opioids for cancer pain, and trials have often had a crossover design, associated with greater bias.^2,3 Moreover, cancer pain can be acute or chronic, and chronic pain is less responsive to opioids.

“One of the problems with cancer pain is that it’s not a single entity.”

— Mellar Davis, MD

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“One of the problems with cancer pain is that it’s not a single entity,” said Dr. Davis. “So, when we talk about managing cancer pain, it’s really quite heterogeneous. It can be related to malignancy, or it can be mostly related to treatment.”

Dr. Davis also questions whether intensity—the common measure of pain—is the outcome that should be measured in patients with cancer. “Maybe it is near the end, in the last 3 months of life, but in patients with stable disease, it may not be,” he said. “In that group, maybe we ought to think in terms of function.”

Intensity is also subjective; patients have extremely varied views of what constitutes intense pain. “Some people will say it’s high because they can’t see their grandkids,” he noted. “They confuse intensity with interference with activity.”

Compounding the problem, some trial outcomes have little to no clinical relevance. A two-point reduction on the visual analog scale or numeric rating scale assumes linearity, but patients may still have significant pain despite that response. Using a 30% and 50% reduction in pain severity is standard in clinical trials and corrects for nonlinearity, but there is still the risk of significant pain in patients who demonstrate these pain reductions.

“Very few trials look at responder analysis,” noted Dr. Davis. “Often they look at the differences between groups, but I think the thing clinicians want to know is the proportion of responders.”

Small numbers of patients in cancer pain trials equate to wide confidence intervals and less confidence in results. Further, meta-analyses have frequently consisted of fewer than 10 trials, leading to a large bias.

“So it’s very difficult to get a sense of where responses occur and, if most trials aren’t placebo-controlled, then it’s also very difficult to separate placebo involvement,” he said.

He pointed out the importance of future trials looking at the utility of opioids—balancing the level of analgesia with the degree of side effects, such as respiratory depression—as not all opioids are the same in regard to risk.

According to Dr. Davis, researchers should reevaluate trial designs and develop cooperative groups to adequately power trials, in addition to clarifying what is meant by “efficacy” in terms of degree and duration of response.

“Now that patients with cancer are living longer, this may be an opportunity to look at enrichment enrollment and randomized withdrawal trial designs in order to really compare opioids,” he said.

Prevention and Management of Opioid Addiction

Dr. Walsh, Chair of the Department of Supportive Oncology at Levine Cancer Institute in Charlotte, North Carolina, expanded on Dr. Davis’ point about the state of the research.

“As we think to the future, we have to advocate for our patients and make sure they get access to these medications.”

— Declan Walsh, MD

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“We have often confused lessons and learned the wrong lessons from particular populations,” he said. For example, the lessons learned from an opioid study in postoperative pain in a patient with cancer have often been applied to the management of chronic cancer pain. As the two are entirely different entities, this has considerably complicated the interpretation of data and studies.

In 2017, just under 50,000 Americans died of drug overdoses,⁴ and in some parts of the United States, life expectancy is now shorter as a result of the opioid epidemic. According to Dr. Walsh, an unfortunate intersection exists among recent advances in cancer pain management, effective use of opioids for cancer pain, and the separate societal problem of abuse of these drugs.

“But patients with cancer are a special population, and we need to state that case very clearly with our politicians, with the media, and with professional organizations,” he said. “They should not be subjected to regulatory barriers that can impair the use of the very important and effective drugs that we already have available to manage these conditions.”

Opioid Use Disorder

The American Psychiatric Association defines opioid use disorder in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, as present in individuals who experience cravings for and failed discontinuation of the drug and have impaired functioning, tolerance, and withdrawals. In addition, opioid use disorder typically occurs in a setting where multiple other drugs are being abused simultaneously, an often underrecognized fact when opioid use issues are reported.

When opioid-dependent individuals stop or reduce their dose of the drug, they may develop a severe flu-like withdrawal syndrome. Dr. Walsh noted that this only implies physical dependence—not psychological addiction—an important distinction.

The clinical management of opioid withdrawal is also complicated by comorbidities (cirrhosis, endocarditis), or other common complications of drug abuse, in addition to the possibility that individuals may be simultaneously withdrawing from other drugs.

“Obviously these are classic issues around addiction,” he said. “But these are not issues for the vast majority of patients with cancer.”

Sloppy Prescribing and Rigid Barriers

A study conducted at the Cleveland Clinic looked at errors in opioid dosage strategy in patients with cancer who were referred to a palliative medicine program, and nearly 80% of the patients referred had significant errors in their opioid prescriptions, evidenced at the time of referral, Dr. Walsh reported.⁵

“And this, of course, can produce pseudoaddiction, where simple bad management of cancer pain causes a ‘craving for the drug’ and drug-seeking behavior, which is an entirely rational response to the particular situation, but is simply caused by ineffective or sloppy prescribing on the part of health-care professionals,” he said. Patients with a new cancer diagnosis accompanied by pain and a history of addiction present a particularly challenging clinical scenario, as do patients with a current or prior cancer and some evidence of opioid use disorder, he added.

Currently, the intersection between the opioid abuse epidemic and the therapeutic use of opioids in cancer pain has challenged the regulatory authorities. The Centers for Disease Control and Prevention released opioid-prescribing guidelines in 2016 that were intended for opioid-naive patients in primary care.

“A whole list of unintended consequences arose, which are now affecting patients with cancer: insurance denials, refusal by pharmacies to fill legitimate prescriptions for patients with cancer, and red flags for physicians who are alleged to be overprescribing opiates,” Dr. Walsh said

These barriers to access have only grown in recent years, even though opioids are necessary to effective pain management of cancer pain: 8 of 10 patients with advanced cancer have moderate to severe pain, 55% of current patients and 40% of cancer survivors experience significant degrees of cancer-related pain, and 10% are continuing to use opiates for their cancer-related pain during the survivorship phase.⁶

According to Dr. Walsh, there is still insufficient education around opioid prescribing for providers, and sloppy prescribing goes on even in palliative care settings, where one might expect a more rigorous approach to opioid management. But ASCO has made clear statements that patients with cancer are a special population who are entitled to these drugs for legitimate use, and arbitrary prescription limits should not be tolerated.⁷

Many opioid deaths are related to polydrug and alcohol abuse, but the actual number of patients who die as a result of properly employed prescription medications is “vanishingly small,” he said.

However, as more and more people are surviving their cancer, a systematic approach—involving drug monitoring programs, pain contracts, screening tools, support services, and urine drug tests—will be necessary, he added.

“As we think to the future, we have to advocate for our patients and make sure they get access to these medications,” said Dr. Walsh. “But we have a responsibility to continue to research and educate about the effects of aggressive opioid use in this setting, and also to consider special interventions for cancer pain survivors, including, importantly, nonpharmacologic interventions.” ν

DISCLOSURE: Dr. Davis reported no conflicts of interest. Dr. Walsh has been compensated for a leadership role for, has received research funding from, and owns stock or other ownership interests in Nualtra; and has received honoraria from, has served in a consulting or advisory role for, and has been reimbursed for travel, accommodations, or other expenses by Tesaro.

REFERENCES

1. Davis M: Opioids for cancer pain: What is the evidence? 2019 Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology Annual Meeting. Abstract PS40. Presented June 22, 2019.

2. Walsh D: Opioid addiction in cancer patients: Prevention and management. 2019 Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology Annual Meeting. Abstract PS41. Presented June 22, 2019.

3. Wiffen PJ, Wee B, Derry S, et al: Opioids for cancer pain—an overview of Cochrane reviews. Cochrane Database Syst Rev 7:CD012592.

4. Scholl L, Seth P, Kariisa M, et al: Drug and opioid-involved overdose deaths: United States, 2013-2017. Morb Mortal Wkly Rep 67:1419-1427, 2018.

5. Shaheen PE, Legrand SB, Walsh D, et al: Errors in opioid prescribing: A prospective survey in cancer pain. J Pain Symptom Manage 39:702-711, 2010.

6. van den Beuken-van Everdingen MH, Hochstenbach LM, Joosten EA, et al: Update on prevalence of pain in patients with cancer: Systematic review and meta-analysis. J Pain Symptom Manage 51:1070-1090.e9, 2016.

7. Page R, Blanchard E: Opioids and cancer pain: Patients’ needs and access challenges. J Oncol Pract 15:229-231, 2019.