Navigating Opioids and Other Strategies for Managing Cancer Pain

Holly L. Geyer, MD

The American Cancer Society estimates that more than 17 million Americans live with cancer,¹ and many of them hurt. Up to 60% of patients undergoing active treatment and a third of cancer survivors report significant pain stemming either from their cancer itself or their cancer treatments.² The most common treatment for significant cancer- related pain is opioid medication. A retrospective analysis of data from 169,162 people who took the National Survey on Drug Use and Health from January 2015 to December 2018 found that 54.3% of the 1243 recent cancer survivors and 39.2% of the 3896 less recent cancer survivors were actively using prescription opioids.³

Use vs Abuse With Opioids

But opioid medications have shortcomings, starting with the potential for abuse. In the analysis, among patients with a more recent history of cancer, prescription opioid misuse was reported in 3.5% and in 3.0% of patients with a less recent history of cancer.³

According to the Centers for Disease Control (CDC), nearly 70,000 Americans died from accidental opioid overdoses in 2019,4 and although only a minority of those deaths stemmed directly from prescription drugs, pain medication was the root cause for many others. Roughly a quarter of patients (95% CI, 13%-38%) who are prescribed opioids for chronic pain misuse their medication,⁵ and about 5% of those patients later transition to heroin. Indeed, about 80% of heroin users misused prescription painkillers before they began using illegal opioids.⁶

Other shortcomings for opioid medications include their ineffectiveness at treating certain types of pain and their diminishing efficacy over time.⁷

“Opioids are entirely appropriate for many patients with acute cancer-related pain, but there’s a major limitation to their utility—bigger even than the risk of addiction or misuse—and that’s tolerance. Users develop it very quickly, so opioids just aren’t effective for most chronic pain, and they don’t even work well for some acute cancer-related pain,” said Robert A. Swarm, MD, Division Chief of Pain Management in Washington University’s Department of Anesthesiology and co-chair the National Comprehensive Cancer Network’s (NCCN) adult cancer pain guideline committee. “Pain management begins with a broad pain evaluation. When does it hurt? Where does it hurt? What does the pain feel like? What makes it better? What makes it worse? Pain is a subjective experience, so you need to start with the patient’s own description, and you need to rely upon the reported changes in a patient’s experience to know if treatment is working.”

Looking Beyond Opioids for Cancer-Related Pain Management

Cancer-related pain arises from both cancers and treatments, and both can create pain in various ways. Pain from cancer itself can involve inflammatory, neuropathic, ischemic, and/or compressive mechanisms at the tumor site or elsewhere. Neuropathic pain arises from damage to neurons—which typically occurs when tumors invade the meninges, spinal cord and dura, nerve roots, plexuses, and peripheral nerves—and can be the most difficult to treat. Surgery, radiation, chemotherapy, and cancer medications can likewise create different types of pain.⁸

Pain management should begin with a pain intensity assessment—with high levels of pain being treated as a medical emergency—and then a comprehensive pain assessment (which is included in the NCCN guidelines) as well as an assessment of a patient’s risk of aberrant drug use (also included).⁹

One advantage of routinely performing comprehensive pain assessments is that they can uncover hidden medical issues that require immediate treatment, issues such as fractures (or impending fractures) in weight-bearing bones, neuraxial metastases with threatened neural injuries, infections, and obstructed or perforated viscus in the abdomen.

If there are no signs that the pain is caused by any condition that needs emergency medical care, the next step is generally to start with a nonopioid analgesic, such as acetaminophen or a nonsteroidal anti-inflammatory drug (NSAID). The exact medication and dose will depend not only on the results of the pain assessment but also on consideration of comorbid conditions and potential drug interactions with the patient’s existing regimen.

“There’s a tendency with [patients with] cancer who have mild or moderate pain to jump straight to opioids, but there are a lot of reasons to try other analgesics first for mild pain, and in combination with opioids for moderate or more severe pain,” said Holly L. Geyer, MD, a Mayo Clinic internist with specialty licensure in addiction medicine. “For one thing, [patients with] cancer tend to get more [adverse] effects from opioids than other patient groups because they are already weakened by heavy disease burden and intense treatment regimens. Also, as treatments improve and [patients with] cancer live longer, more of them require pain management strategies that are better for long-term use.”

According to Geyer, the tendency to use opioids immediately on patients with metastatic cancer arose when cancer treatments were less effective and longterm survival rates were lower. There was less reason to worry about a treatment’s long-term efficacy or about the risk of addiction. Indeed, many thought it cruel to withhold opioid medications from people with serious pain and little time to live, even the few weeks it took to establish that other analgesics did not work was deemed too long. So, opioids became the standard of care for cancer, including among patients who were expected to live indefinitely.

For mild cancer-related pain, opioids are now considered an appropriate second line of treatment if initial treatment with acetaminophen and/or NSAIDs does not work, but there are other options.

“There is a range of alternatives that can be added to or used instead of nonopioid analgesics,” Geyer said. “There are topical pain medications such as lidocaine patches and nerve blocks and anticonvulsive medications such as gabapentin and antidepressants, all of which can be very effective. There are also nonpharmaceutical interventions ranging from meditation and yoga and tai chi to physical and occupational therapy, although it can be difficult to get patient buy-in on treatments that require effort.

“When you’re struggling with a cancer diagnosis and a taxing treatment regimen, the last thing you might want to do is undergo physical or occupational therapy, particularly given that they can actually cause more pain when you’re actually doing them. However, such practices can greatly reduce pain and increase patient function, depending on the source, so they’re definitely worth discussing, particularly with patients who are losing their ability to perform essential tasks.”

Nonpharmaceutical interventions such as physical therapy have one other drawback— at least while the COVID-19 pandemic continues—they tend to require frequent face-to-face interaction.

Initially, of course, the pandemic had serious effects on all pain management. Practices closed. Patients could only access their caregivers via telephone, so many caregivers transitioned patients from in-office treatments to opioids. Geyer believes that only time will tell if this lack of access to more appropriate pain management alternatives played a role in 2020's dramatic surge in opioid deaths, which exceeded 50% in some states.

Over the long run, however, Swarm believes the effects of the pandemic may turn out to be positive, at least if Medicare and other insurers continue to allow appropriate use of telemedicine, which spares patients not only the time it takes to drive to a caregiver’s office but also the discomfort that such trips can inflict upon people who are already in pain.

For now, the pandemic is having minimal impact on most treatments that caregivers can offer, and, as Geyer said, there are a lot of options that can be tried as monotherapy or in conjunction with nonopioid analgesics, opioids, or both.

Several studies indicate that topical pain treatments such as lidocaine can be an effective pain treatment for many patients with cancer. Investigators at an Australian cancer center, for example, prescribed 5% lidocaine patches for 97 patients who were experiencing pain from surgery, cancer itself, or postherpetic neuralgia. Reviewers classed lidocaine analgesic efficacy as ‘potent’ in 38% of patients with postherpetic neuralgia, 35% with postsurgical pain, 27% with neuropathic pain after other treatments for cancer, and 12% with neuropathic pain attributed to cancer alone. Treatment lasted longer than 1 month in 52 patients, longer than 2 months in 29, and longer than 1 year in 13.¹⁰

Nerve blocks also have a long track record for effectively treating several types of cancer- related pain. In one trial dating all the way back to 1977, alcohol celiac plexus nerve blocks were done in 100 patients, including 97 with intractable abdominal pain from cancer. Good to excellent pain relief was achieved in 94% of patients. Complications and adverse effects other than postural hypotension were rare (10 patients), but there was 1 case of partial leg paralysis.¹¹

Nerve blocks work by numbing nerves and interrupting pain signals before they reach the brain. Anticonvulsants work differently, but they can also be a potent tool in reducing pain. In an Italian study of 120 consecutive patients with neuropathic pain due to cancer that was already partially controlled with systemic opioids, analysis of covariance on the intent-to-treat population showed a significant difference in average pain intensity between gabapentin-treated patients (pain score, 4.6) and placebo-group patients (pain score, 5.4; P = .0250). Adverse events were similar in the gabapentin and placebo arms of the trial.¹²

For some types of pain, particularly that caused by bone metastases, radiation therapy can provide significant relief. A study of 91 Japanese patients treated with radiotherapy for painful bone metastases found that mean pain scores dropped from 7.8 points at 5 days after treatment to 1.1 at 40 days after radiotherapy (P < .001).¹³

The evidence for adding antidepressants to a pain management regimen is mixed. Although some studies have found a benefit to using either tricyclics or selective serotonin reuptake inhibitors with other analgesics, others have not. That said, a 2017 review of published studies concluded that the weight of the evidence supports the use of antidepressants not only for depression in patients with cancer but also as an adjuvant treatment for cancer-related symptoms, including pain.¹⁴

There is even less evidence to support the use of cannabis and its derivatives. Anecdotal evidence of their pain-killing power abounds, but controlled studies are vanishingly rare because, despite the relaxation of state cannabis laws, the ongoing federal prohibition constrains the flow of research dollars.

“Consider an approved drug like oxycodone,” Swarm said. “It has a single chemical formula that’s perfectly reproduced in factories. We have trials that tell us how large a dose to give and when to give it. We know what pain it’s likely to help and how much it’s likely to help that pain. We also know what adverse events it causes and how to address those events.

“We don’t know any of that with cannabis. We don’t know what’s in any batch because every strand is different.... We don’t have much dosing information about any of those products or much information about their efficacy or much information about adverse events…. Health care providers don’t have the information to provide specific guidance to a patient who wants to try cannabis for pain.”

There is more evidence, though, to support the use of nonpharmaceutical interventions such as yoga or physical therapy, but, again, much of the positive evidence is anecdotal.

When to Prescribe Opioids and When to Stop

The most common treatment option for patients with cancer-related pain is some form of opioid analgesic, and the experts interviewed for this story, along with published guidelines for treating cancer pain, all stressed that such medications are perfectly appropriate for many patients whose cancer-related pain does not respond to nonopioid analgesics.

Before prescribing such medications, physicians should always establish whether patients have taken enough opioids in the past to develop a tolerance—opioids don’t work well enough to be recommended in patients who have developed tolerance— and perform a test designed to assess each patient’s risk of abusing such medications.

In patients who have yet to develop tolerance, opioid treatment can be very effective in the short term. A research review for the Education Book series from the American Society of Clinical Oncology (ASCO) estimated that about 75% of all patients with cancer respond to opioid treatment and that such treatment typically reduces pain intensity by 3 points on a standard, 10-point self-assessment of pain.¹⁵

The NCCN9 and ASCO16 both have comprehensive pain management guidelines that include instructions for establishing and adjusting opioid analgesic dosages and for providing continuous monitoring (TABLE). Physicians should also understand the regulations pertaining to opioid analgesics in their state.

“Oncologists should not be so reluctant to prescribe opioid medications that they pass everyone who doesn’t respond to nonopioid analgesics on to pain specialists. Opioids are the correct treatment for many [patients with] cancer and there are good guidelines for using them properly,” said Jonathan Treem, MD, a hospice and palliative care specialist at University of Colorado Medicine.

In cases where patients with cancer suffer from chronic pain and physicians believe that opioids provide the best relief, the CDC has guidelines for managing long-term opioid use,¹⁷ but Treem says that opioids rarely constitute the best treatment option for long-term use.

“There is a risk of addiction and also the risk of behaviors that fall somewhere between addiction and appropriate use, and those risks increase with duration of use. There’s diminishing efficacy. And there are long-term health risks that we don’t fully understand, but studies of all-cause mortality show that long-term opioid users die significantly earlier than you’d expect,” said Treem.

“In the vast majority of cases, when you’re switching from acute pain treatment to chronic pain treatment, you should switch away from opioids, even if your patients are reluctant to change. If you can’t find a long-term treatment regimen that provides adequate relief, you can always consult with a pain specialist.”

Indeed, the experts interviewed for this story emphasized that although clinical oncologists and hematologists should understand and be able to apply the basic strategies for treating cancer pain, it is imperative to seek help from pain specialists when patients do not respond to these strategies.

“There are good guidelines out there that walk practitioners step-by-step through the basics of pain management, and there are good continuing education conferences that can provide further information,” said Geyer. “However, when tough cases arise and it’s unclear how to proceed, it’s totally appropriate to turn to specialists.”

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