Efforts to address opioid epidemic must limit overuse without restricting access for cancer pain control

The number of drug overdose deaths involving opioids has quadrupled since 1999, according to the CDC. Approximately 91 Americans die of opioid overdose each day.

America’s opioid epidemic has complicated the treatment of patients with cancer, one-third of whom experience moderate to severe pain.

Opioid analgesics provide relief for up to 90% of patients with pain. However, psychological distress, undergoing multiple invasive procedures and a lack of coordination among physicians can make cancer survivors particularly vulnerable to opioid dependency.

“The lack of physician training and education about the pharmacology of these drugs and how to safely use them is truly appalling and a huge failure of medical education in this country,” Diane E. Meier, MD, FACP, professor in the department of geriatrics and palliative medicine at Icahn School of Medicine of Mount Sinai, director of the Center to Advance Palliative Care and a HemOnc Today Editorial Board Member, told HemOnc Today. “It is a big contributor to the opioid epidemic.”

Growing recognition of that epidemic — and patient fear regarding dependency — may prevent some patients with chronic cancer pain from getting needed relief.

HemOnc Today spoke with palliative care specialists and pharmacologists about how the overprescription of opioids for cancer pain has contributed to the national epidemic, how fear of opioid addiction may prevent patients from receiving proper pain management, and what programs have been set in place to reduce unnecessary opioid prescriptions.

Opiate pharmacology

Morphine and oxycodone are the most frequently used opioids for cancer pain.

WHO’s cancer pain ladder recommends adults start with nonopioids, like aspirin and acetaminophen. If pain persists or becomes stronger, patients can progress to weak opioids, like codeine, followed by stronger opioids, like morphine, until pain free.

WHO also recommends opioids be given on a regular schedule to maintain freedom from pain. This approach can lead to an 80% to 90% success rate.

Different cancer treatments lead to a variety of pain syndromes. For instance, surgery can cause neuralgia or lymphedema; radiation therapy could lead to cystitis, osteoradionecrosis or abdominal pain; and chemotherapy can induce muscle cramps, osteoporosis and myalgia.

“Cancer is certainly not the only serious illness that causes disabling pain, but it is one that both the public and professionals are very well aware of,” Meier said. “There is a strong public consensus that cancer pain should be treated so people can function and have an acceptable quality of life. The bottom line is you want patients to have a life worth living.”

Better pain control can be achieved with opioids, Jai N. Patel, PharmD, BCOP, chief of pharmacology research at Levine Cancer Institute of Carolinas HealthCare System and a HemOnc Today Editorial Board Member, said in an interview.

“For this reason, these drugs are the gold standard for treating cancer-related pain of moderate to severe intensity,” he said. “We have an effective selection of opioids, but everyone responds differently — most of the time it is trial and error before we finally choose the right drug at the right dose that actually works.”

Chronic dosing of opioids leads to tolerance, sometimes causing the need for dose escalation. However, usually dose escalation is necessary because of underlying disease progression, Meier said.

“Tolerance develops rapidly to side effects such as sedation and nausea,” she said. “It does not develop to the major side effect — constipation — and it rarely develops to the desired effect, analgesia.”

Prescription patterns

The CDC reported that health care providers wrote 259 million prescriptions for opioids in 2012, enough for every adult in the United States to have a bottle of pills.

Further, opioid prescriptions per capita increased 7.3% from 2007 to 2012. Rates of opioid prescribing varied greatly across states in ways unexplained by the underlying health status of the population, highlighting the lack of consensus among clinicians on how to use opioids.

The average opioid dose for cancer pain is 90 mg to 120 mg. This represents an increase from the average 30-mg dose used in the 1960s and 1970s, according to Mellar P. Davis, MD, FCCP, FAAHPM, director of palliative care services at Geisinger Health System in Danville, Pennsylvania.

Source: Geisinger.

“One reason [for this increase] is we may be more dependent on opioids for pain than we should be, and we should have instituted other interventions sooner,” Davis told HemOnc Today. “Another reason is that patients with advanced disease are living much longer than they used to.”

The growing number of cancer survivors is changing opioid use, Paul A. Glare, MBBS, FRACP, FACP, director of the Pain Management Research Institute at The University of Sydney in Australia, told HemOnc Today.

“Cancer is becoming a chronic disease for some people, who can be maintained on treatment for a long time,” Glare said. “People with cancer will have pain and be exposed to opioids longer.”

A study by Sutradhar and colleagues highlighted the impact long-term opioid use can have on a cancer survivor. Researchers evaluated health records of 8,600 cancer survivors at least 5 years past their diagnosis (median, 10 years) in Ontario, Canada.

Survivors demonstrated a significantly higher crude rate of opioid prescriptions than controls (relative rate = 1.22; 95% CI, 1.11-1.33), which persisted whether they were 5 to 10 years past diagnosis (relative rate = 1.19; 95% CI, 1.04-1.36) or 10 years or longer past diagnosis (relative rate = 1.24; 95% CI, 1.09-1.42).

“For some survivors, being cancer free doesn’t necessarily mean being pain free, for a variety of reasons,” Sutradhar told HemOnc Today. “Pain lingering during survivorship could be associated with factors such as type and invasiveness of tumors, the type of treatments, other illnesses that may coincide with the cancer, as well as other aspects of the patient’s life, such as their age, work situation, socioeconomic status and so forth.”

Socioeconomically disadvantaged populations are more at risk for opioid dependency, which, may deter oncologists from prescribing opioids to certain populations.

For instance, a study by Joynt and colleagues showed patients from lower socioeconomic regions were less likely to receive opioids than those from more affluent areas for the same levels of pain.

Physicians most frequently prescribed opioids for patients from the highest status quartiles of household income (47.3% vs. 40.7%; P < .001) and educational level (46.3% vs. 42.5%; P = .01).

Black patients (adjusted OR = 0.73; 95% CI, 0.66–0.81) and those from poorer areas (adjusted OR = 0.76; 95% CI, 0.68–0.86) appeared less likely to receive opioids.

“It’s a little more anxiety provoking if the patient is coming from an environment where there is a sense of greater prevalence of abuse,” Charles F. von Gunten, MD, PhD, medical oncologist and vice president of medical affairs, palliative medicine at OhioHealth, told HemOnc Today. “But, it doesn’t matter who the patient is. ... We should be prudent, but not deprive a patient of the pain relief he/she deserves for their cancer pain.”

Overuse, side effects

The growing concern about the adverse effects of opioids and the risks for misuse, abuse and overdose can affect how patients with cancer pain are treated.

“Everyone knows opioids carry all sorts of side effects and risks,” Meier said. “Constipation is a universal side effect and can become a life-threatening condition, particularly among older patients who have multiple chronic conditions or patients with cognitive impairment.”

Other side effects, such as sleepiness, nausea and itching, may be temporary.

“These side effects — except for constipation — tend to wear off after a few days, and this is something important for clinicians and patients to understand,” Meier said. “The side effects aren’t trivial but, when someone has disabling pain, we have to also figure out how to deal with these side effects.”

Many patients with cancer also may be wary to take opioids because of the growing acknowledgement about their risks.

“This requires us to speak with the patients and inform them opioids are considered standard of care,” Patel said. “We need to tell them that, with appropriate monitoring, titrating of medications and close assessments, they will be fine.”

Data suggest around 10% of people prescribed opioids become addicted — defined as psychologically dependent despite harm to self or others — a small percentage of whom were originally prescribed opioids for cancer pain.

“It needs to be put in the context that only a small percentage [of patients with cancer] truly end up becoming addicted or harmed,” Glare said.

Data from the 2015 National Survey on Drug Use and Health showed 91.8 million (37.8%) Americans had a prescription for opioids. Of these, 12.5% self-reported misuse, 63.4% of whom did so to relieve pain.

In a study published in October in Journal of Clinical Oncology, Lee and colleagues showed that the risk for new persistent opioid use and daily opioid use the year after surgery varied according to treatment received. Among 68,463 patients who underwent curative-intent surgery and filled opioid prescriptions, incidence of new persistent opioid use was 10.4% (95% CI, 10.1-10.7).

Undergoing adjuvant chemotherapy in addition to cancer surgery significantly increased the likelihood of new persistent opioid use among patients with breast cancer (OR = 2.4), melanoma (OR = 2.6), colorectal cancer (OR = 2.3), hepato-pancreato-biliary/gastric cancer (OR = 2.2) and thoracic cancer (OR = 2.1). Adjuvant radiation increased risk among patients undergoing melanoma (OR = 4.7; 95% CI, 2.4-9.2) and thoracic (OR = 2.1; 95% CI, 1.4-3) surgeries.

Clinicians should consider a patient’s need before prescribing opioids.

“There have been a lot of patients, even in my practice, who have had painless cancer that has been removed, but they have chronic back pain or migraines,” Glare said. “We often make special allowances for patients with cancer to have opioids, which could, in turn, potentially include a lot of patients for whom use is not appropriate.”

Appropriate monitoring could become staggered, increasing risk for addiction.

“We can’t prescribe an opioid and say we will see you in 3 months or even 1 month later,” Patel said. “This does not allow for optimal pain control.”

It is crucial clinicians step in at the time of opioid dependency.

“If you have a patient who has a substance use disorder, find another way to manage their pain any way that is safe for them, and explain it to them,” Davis said. “This is another important issue in the opioid epidemic — you can’t just throw the baby out with the bath water. You need to maintain your relationship with your patient and get them the help they need.”

Alternative pain control

Opioids are not the only proven means of addressing cancer pain.

“There is a whole array of potential modalities to treat pain,” Davis said. “We’ve just been highly dependent on opioids to treat cancer pain.”

Alternative pain options ranging from acupuncture to cognitive behavioral therapy, yoga and exercise have shown promise for mitigating cancer pain.

Hu and colleagues conducted a systematic review that showed the addition of acupuncture to traditional drug therapy better managed cancer-related pain among 1,639 individuals.

Although acupuncture alone did not improve symptoms, the combination increased pain remission rate, quickened onset to pain relief, lengthened pain-free duration and bettered quality of life compared with drug therapy alone.

Self-management programs may be effective means of address pain.

“At my clinic, we have had patients come in with chronic nonmalignant pain and 60% of them are on opioids,” he said. “When they undergo self-management, we work with them on an individual basis to get it down to 30% using opioids. It is possible to deprescribe opioids, but you need to replace it with other means of managing pain.”

The combination of coanalgesics — or any adjuvant nonopioid pain medication, such as bisphosphonates for bone pain, muscle relaxants or corticosteroids — and opioids can also help patients achieve better pain relief, von Gunten said.

“Oncologists know that if you combine drugs with different mechanisms of action you get better anticancer therapy,” Glare said. “The same is true in cancer pain management and medicines.”

Pain management is multidimensional.

“Opioids are there to address the biomedical component of pain, but pain is also social and psychological,” Glare said. “Unless you address the other dimensions, you are never going to control it properly.”

The fact Western society is biomedically oriented contributes to overuse.

“Societies with a strong spiritual background used different mechanisms of their religion or spirituality for pain,” Davis said. “Peopled developed a belief system to transform their pain into something that is meaningful spiritually. Western society has changed its spiritual background, letting materialism play a role in increased opioid use.”

Curbing opioid misuse

National medical societies and organizations are making strides to intensify research and provide guidance to address the opioid crisis.

For instance, the National Institute on Drug Abuse partnered with industry to develop an intranasal naloxone formulation (Narcan Nasal Spray, Adapt Pharma) to reverse an overdose.

The NIH also is working with private partners to develop stronger formulations of mu-opioid receptor antagonists to counteract opioids. Further, the agency has partnered with Titan and Braeham Pharmaceuticals to develop new formulations of existing medications to improve compliance with buprenorphine — an underutilized drug to help treat opioid substance use disorder — by producing a 6-month implant.

“I’m very pleased to see the NIH is doing something to develop new varieties of analgesics with fewer risks — a key step to address this huge public health crisis that matters to Americans,” Meier said.

Organizations also have put forth guidelines to deter overprescribing and decrease likelihood of addiction.

The CDC updated guidelines for prescribing opioids for chronic pain outside of active cancer treatment, palliative care and end-of-life care. The guidelines provided recommendations for when to initiate or continue opioids for chronic pain; opioid selection, dosage, duration, follow-up and discontinuation; and assessing risk and addressing harms of opioid use.

Von Gunten said the recommendations are a step in the right direction.

“Everybody in oncology should be reassured that no one — not the state medical board, not the FDA and not the CDC — wants to prevent patients with cancer from getting the opioids they need,” von Gunten said. “They don’t want them to get more than they need; they just want them to get what they do need.”

A main component of the guideline update was the use of immediate-release opioids, Patel said.

“These agencies are suggesting to only use immediate-release opioids upfront and prescribe the lowest effective dose for shortest time possible, which is between 3 to 7 days,” he said.

Although the guidelines apply to patients with chronic pain unrelated to active cancer treatment, it’s unclear exactly who that population is, Patel said.

“Some patients might not be under active treatment but still have active cancer, and some may be at high risk for disease recurrence and have pain as a consequence of their treatment,” he said.

In light of greater guidance to tackle the opioid epidemic, ASCO has worked to ensure balance, so that patients with cancer are not restricted from receiving pain medication.

A 2016 statement from the society suggested:

• providers should have evidence-based guidance on safe and effective opioid prescribing tailored by specialty;
• prescription limits that would artificially impede access to medically necessary treatment for patients with cancer are not appropriate;
• efforts should focus on patient education and safe storage and disposal of prescription medication; and
• authorized collection sites should be readily available to patients to decrease the availability of unused or unwanted opioid drugs.

“Often we blame the drug rather than the way we are using it and, as a result, opioid use can become more restrictive, making it more difficult to manage cancer pain,” Davis said.

A ‘public health emergency’

In March, President Donald J. Trump signed an executive order that established the Commission on Combating Drug Addiction and the Opioid Crisis.

That committee recommended the president declare the opioid epidemic a national emergency. In October, Trump responded by instead calling the epidemic a “public health emergency,” promising funding to state governments for antiaddiction medication.

Following that declaration, FDA Commissioner Scott Gottlieb, MD, released a statement that reaffirmed the agency’s commitment to addressing the epidemic and outlined possible solutions to reduce inappropriate opioid exposure.

Among these potential solutions include packaging that would limit the number of pills dispensed or that would track the number of doses taken.

“We believe that innovation in packaging, storage and disposal could have a meaningful impact on preventing or deterring misuse, abuse or inappropriate access to prescription opioids — especially when coupled with additional efforts that the FDA and others are undertaking to reduce the scope of the opioid epidemic,” Gottlieb said in the statement.

Keeping medications safe — through tamper-resistant packaging and return boxes — is an important solution.

“In the patients we are treating, the opioids are not causing addiction,” von Gunten said. “We’re trying to prevent misuse of opioids by others and limit their access to them, because it is an access issue.”

Prescription drug monitoring programs — state-based electronic databases that track controlled substance prescriptions — offer an intervention to help improve painkiller prescribing, inform clinical practice and protect patients at risk.

In March 2016, Massachusetts became the first state to limit opioids to a 7-day supply for a first-time prescription. The law requires physicians and pharmacists to check the state’s prescription monitoring program before prescribing certain opioids.

Since then, nine other states have passed similar laws and a bill with a 7-day limit has been introduced in Congress.

Last month, CMS announced a policy that would allow states to design demonstration projects that increase access to treatment for opioid use disorders. State Medicaid programs can reimburse for substance use disorder treatment provided at certain inpatient facilities.

“Previous policies ignored the growing urgency of the national opioid epidemic and instead put onerous requirements on states that ultimately prevented individuals from accessing these needed services,” Seema Verma, MPH, CMS administrator, said in a press release. “This new demonstration policy comes as a direct result of the president’s commitment to address the opioid crisis.”

Physician, patient education

Beyond regulatory efforts, meaningful changes in the opioid epidemic will depend on physician and patient education.

“More education is needed — beginning in medical and nursing school, and even at the undergraduate level — that is incorporated into a mandatory curriculum,” Meier said. “For graduate medical and nursing programs, there still is no mandatory training on safe and effective opioid prescribing, and there urgently needs to be.”

Texas, New York and California have passed laws requiring midcareer mandatory training on opioid prescribing. Although data are not available on whether these mandatory laws have curbed inappropriate prescribing, it is still a step in the right direction, Meier said.

More education on the difference between addiction and dependence also is needed, Meier said.

“You can’t quit most drugs, including opioids, cold turkey,” she said. “The problem is that many physicians and patients don’t understand a patient needs to reduce the dose slowly over a week or 2.”

This is especially a problem for patients prescribed a short course of opioids following surgery.

“We don’t know what percentage of these patients can actually taper without also going through a difficult period of withdrawal,” Meier said. “We don’t know how many people this happens to or what their genetic biomarkers are, but we do know it happens to some people.”

Safe storage of opioids is a key component of patient education.

The 2015 National Survey on Drug Use and Health showed that nearly 60% of adults who misused opioids did so without a prescription — 40.8% acquired opioids from friends or relatives for free and 12.8% acquired them from drug dealers.

“We need to caution patients about where they keep their opioids and to educate all of our patients, regardless of socioeconomic status, to keep their opioids in a safe, locked place,” von Gunten said. “I make plenty of home visits and it’s amazing how many people keep their medicines out in the open for anybody to walk off with.”

Education also should aim to rid of the stigma associated with opioids, which can prevent patients with cancer from accessing appropriate pain medication, and also prevent patients with opioid dependency from seeking needed help.

“There is enormous stigma in this country associated with using opioid analgesics and people who legitimately need them — not only cancer patients, but other groups, such as people with sickle cell disease — who are now labeled as manipulative drug seekers,” Meier said. “In medicine we prescribe risky drugs and treatments all the time but we must balance the benefits and the risks of every treatment — this is what it means to practice medicine.”

The FDA also has announced plans to address this stigma by publicly speaking about proper opioid use.

“Misunderstanding around the profile of these products enables stigma to attach to their use,” Gottlieb said in an oral testimony before the House Committee on Energy and Commerce Hearing, “Federal Efforts to Combat the Opioid Crisis: A Status Update on CARA and Other Initiatives.”

“This stigma serves to keep many Americans who are seeking a life of sobriety from reaching their goal,” Gottlieb added. “In this case, in the setting of a public health crisis, we need to take a more active role in challenging these conventions around medical therapy.”

Anyone who uses opioids for a period will develop a physical dependence, Gottlieb added.

“Even a cancer patient requiring long-term treatment for the adequate treatment of metastatic pain develops a physical dependence to the opioid medication,” he said. “That’s very different than being addicted.”

Ultimately, pain management education should be sophisticated and not rely exclusively on opioids, Glare said.

“More thought needs to be given to the patient’s prognosis, overall health status and goals,” he said. “Opioids may be fine to prescribe to someone recovering from surgery or in hospice, but it may not be the best way to treat pain in someone who is a cancer survivor or has long-term cancer. These people need a different approach to pain.” – by Melinda Stevens

Click here to read the , “Should all patients with cancer undergo an addiction risk assessment prior to receiving opioids?”

References:

ASCO Policy Statement: Opioid Therapy: Protecting Access to Treatment for Cancer-Related Pain. Available at: www.asco.org/sites/new-www.asco.org/files/2016-ASCO-Policy-Statement-Opioid-Therapy.pdf. Accessed on Nov. 15, 2017.

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Joynt M, et al. J Gen Intern Med. 2013;doi:10.1007/s11606-013-2516-z.

Lee J S-J, et al. J Clin Oncol. 2017;doi:10.1200/JCO.2017.74.1363.

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For more information:

Mellar P. Davis, MD, FCCP, FAAHPM, can be reached at mdavis2@geisinger.edu.

Paul A. Glare, MBBS, FRACP, FACP, can be reached at paul.glare@sydney.edu.au.

Diane E. Meier, MD, FACP, can be reached at diane.meier@mssm.edu.

Jai N. Patel, PharmD, BCOP, can be reached at jai.patel@carolinashealthcare.org.

Charles F. von Gunten, MD, PhD, can be reached at charles@pallmed.us.

Disclosures: Patel reports a consultant role with Janssen Pharmaceuticals and research funding from Janssen Pharmaceuticals and Myriad Genetics. Davis, Glare, Meier and von Gunten report no relevant financial disclosures.