The Pains of Opioid Prescribing

The United States is in a state of emergency: The Centers for Disease Control and Prevention (CDC) estimates that 91 Americans die each day from an opioid overdose.1 Over the past two decades, the amount of prescription opioids sold in the U.S. has quadrupled, contributing to the current epidemic of opioid misuse and abuse.

In response, federal agencies, medical organizations, and health-care professionals are working together to more closely monitor and regulate opioid prescriptions to prevent abuse. For patients with cancer or hematologic conditions who rely on opioids to manage their disease-related pain, though, the actions may have the unintended effect of limiting access to necessary drugs.

“Patients [who] suffer from pain require treatment – that sounds simple, but the truth is that our patients suffer significantly from pain related to their hematologic conditions, and this pain affects their ability to function,” Amanda M. Brandow, DO, MS, associate professor of pediatrics in the section of hematology/oncology at Medical College of Wisconsin, told ASH Clinical News. “They have a medical indication for pain treatment, and opioids are the backbone of therapy to relieve their suffering.”

Medical societies and research organizations are creating new guidelines to inform pain management in patients with hematologic conditions. For example, the American Society of Hematology (ASH), with input from physicians and patients, is currently developing clinical practice guidelines for the management of acute and chronic complications of sickle cell disease – including the care and management of pain.

As new guidelines are introduced, hematologists and oncologists must ensure that their patients are not left without access to opioids for pain management. ASH Clinical News spoke with Dr. Brandow and other health-care professionals about the factors that led to the opioid crisis and the struggle to balance the risks and benefits of prescribing opioids.

How Did We Get Here?

Many factors over the past several decades came together to create the “perfect storm” that led to the current opioid crisis, according to Daniel Clauw, MD, director of the Chronic Pain and Fatigue Research Center at the University of Michigan.

When the U.S. Food and Drug Administration (FDA) gained much of its regulatory authority in the 1960s, scientific panels were convened to assess which drugs were effective for which conditions, and determined that opioids were effective for treating both acute and chronic pain, Dr. Clauw explained.

“Since the 1960s, opioid labels have stated that these medications could be used to treat either type of pain but, in practice, clinicians were not using them for that purpose – except in patients with cancer-related pain or SCD-related pain,” he said. “Every time a manufacturer came out with a new version of an older opioid, the FDA would look to the past evidence and come to the conclusion that, because oxycodone works for acute and chronic pain, the new drug could also be marketed for any acute or chronic pain condition.”

“Practitioners believed that if you had to ask about it and put it in a chart, then there was some imperative that you should be treating it.”

—Daniel Clauw, MD

In 1980, the New England Journal of Medicine published a short letter to the editor written by two doctors from the Boston Collaborative Drug Surveillance Program of Boston University Medical Center.2

The now-infamous letter downplayed the rate of addiction in patients treated with narcotics in hospitals, stating that, in a group of nearly 12,000 hospitalized patients, there were only four cases of “reasonably well documented addiction in patients who had no history of addiction.” The authors concluded that, “despite widespread use of narcotic drugs in hospitals, the development of addiction is rare in medical patients with no history of addiction.”

In the 1990s, pain experts started a campaign to make patient pain “more visible,” inadvertently opening the door for potential overprescribing of pain-management medications. Organizations like the Veterans Health Administration implemented a new National Pain Management Strategy to prevent patient suffering and lobbied for pain to be considered “the fifth vital sign.”

Pharmaceutical companies were there to answer the call for increased management of patient pain. In 1995, Purdue Pharma gained regulatory approval for OxyContin tablets, a controlled-release oral formulation of oxycodone hydrochloride, “for the management of moderate to severe pain where use of an opioid analgesic is appropriate for more than a few days.”3 The product label stated that the controlled-release formulation had a lower potential for abuse and warned that crushing the tablets would disrupt the drug’s controlled-release properties.

According to Dr. Clauw, Purdue Pharma was one of the first drug companies to promote opioids for chronic, non-malignant pain, even starting a marketing blitz.

Soon after, The Joint Commission (formerly the Joint Commission on the Accreditation of Healthcare Organizations, or JCAHO) introduced standards to help organizations better care for patients with pain, calling on hospitals to educate practitioners about assessing and managing pain.4

“Practitioners believed that if you had to ask about it and put it in a chart, then there was some imperative that you should be treating it,” Dr. Clauw said. “Combined with some accomplices in academia who said opioids were good for chronic pain and not addictive, that led to a dramatic increase in prescribing opioids for chronic pain.”

Nearly 40 years later, in 2017, the New England Journal of Medicine published a response to the 1980 letter, claiming that the original was “heavily and uncritically cited” as evidence that addiction was rare. According to the 2017 response, citation of the original letter in other research “contributed to the North American opioid crisis by helping to shape a narrative that allayed prescribers’ concerns about the risk of addiction associated with long-term opioid therapy.”5

“There was a general lessening of the concerns about using opioids,” Dr. Clauw said. “This led to skyrocketing numbers of opioid prescriptions for both acute and chronic pain.”

Regulatory Response

Although the opioid crisis has gained public attention, solutions to combat it are only in the beginning stages, according to Patricia Kavanagh, MD, associate professor of pediatrics at Boston University School of Medicine and co-chair of the Emergency Department Sickle Cell Care Collaborative.

In February 2016, the FDA released its Opioid Action Plan, outlining steps it would take to combat the crisis.6 Among the planned actions were:

  • convening an expert advisory committee to approve any new drug application for an opioid that does not have abuse-deterrent properties
  • developing warnings and safety information for immediate-release opioid labeling
  • strengthening post-market requirements
  • updating its Risk Evaluation and Mitigation Strategy program for opioids
  • expanding access to abuse-deterrent formulations to discourage abuse
  • supporting better treatment
  • reassessing the risk-benefit framework for opioid use

“As legislation and work continue to evolve and address the opioid crisis, it will be important to keep [patients] at the forefront.”

—Amanda M. Brandow, DO, MS

The plan appeared to be in full effect in June 2017, when the FDA requested that Endo Pharmaceuticals remove its abuse-deterrent reformulation of extended-release oxymorphone hydrochloride (Opana ER) because of the potential for the drug to be misused.7 According to the agency’s news release, the decision was based on data showing a significant shift in the route of abuse of the reformulated drug from nasal to injection, which was associated with outbreaks of HIV and hepatitis C, as well as cases of thrombotic microangiopathy. (For a firsthand experience managing this complication, read this month’s Editor’s Corner by Alice Ma, MD.)

“We are facing an opioid epidemic – a public health crisis, and we must take all necessary steps to reduce the scope of opioid misuse and abuse,” FDA Commissioner Scott Gottlieb, MD, said about the unprecedented decision. “We will continue to take regulatory steps when we see situations where an opioid product’s risks outweigh its benefits, not only for its intended patient population, but also in regard to its potential for misuse and abuse.”

The CDC also released guidelines for prescribing opioids for chronic pain – outside of active cancer treatment, palliative care, end-of-life care, and treatment of patients with SCD.8 The guidelines address when to initiate or continue the use of opioids for chronic pain; how to select opioid type, dosage, and duration; and how to assess risk and harms of opioid use.

“Unfortunately, I do not think most people practicing in primary care and the emergency department (ED) are reading the fine print,” Dr. Kavanagh said. “If you have cancer or sickle cell pain, there are few options proven effective to alleviate the pain. These broad-stroke guidelines have left a challenge for those of us in the oncology and sickle cell world to advocate for our patients.”

As the events leading to the opioid crisis were multifactorial, Dr. Kavanagh said, any effective solution will have to be as well.

Challenges of Pain Management

SCD is associated with debilitating acute pain, Dr. Brandow explained. This acute pain – called sickle cell or vaso-occlusive crisis – can occur without warning and can be intense, frequently sending people to the ED. For such patients, opioids are often the backbone of pain management, and using them at home means that patients can avoid going to the ED or acute-care centers.

“We definitely understand the need for limitation and proper use of opioids, but the more restrictions we put on patients who need opioids to treat their conditions at home, the more it has a downstream effect of increased suffering and reliance on the ED, when [patients] could have potentially treated their pain at home,” Dr. Brandow explained. “We can’t lose sight of the fact that patients living with these chronic conditions need pain treatment.”

The lack of alternatives to opioids also highlights the necessity of the drugs. According to Dr. Brandow, there is no body of evidence to support the use of other medications for sickle cell pain, though, in recent years, research has shed more light on the pain that people with SCD experience, with the ultimate goal of identifying “opioid-sparing” pain-management options.

“In the past, people with SCD only lived into their teens or early 20s,” Dr. Clauw noted. “Now that they are living longer, it appears that the type of pain they experience is changing – from acute pain to a more centralized pain.”

When sickle cell crises begin, opioids work well to manage the acute pain, he said. However, as with many chronic pain conditions, the type of pain – and the therapy needed to address it – changes over time. “In the beginning, pain was likely due to damage or inflammation in peripheral tissues, but as the disease continues, pain becomes driven by changes in the brain and central nervous system – a type of pain called central sensitization,” he explained. “This type of pain is coming more from the brain and spinal cord than the peripheral nervous system, and opioids don’t seem to work for that type of pain.”

When people use opioids to treat long-term, chronic pain, they are likely to develop tolerance to the medications.

“The longer you are on opioids, the more you need,” Dr. Clauw explained. “Your brain will reduce the number of opioid receptors, which means you need more opioids to have the same effect. And, as doses increase, the risk for death from opioid overdose increases accordingly.”

Patients with SCD also can have difficulty finding practitioners who are familiar with their needs. Given the widespread concerns about opioid abuse, practitioners can also be quick to label patients with SCD as displaying drug-seeking behavior.

“The vast majority of patients with SCD are not drug seeking; they are appropriately seeking care for a disease they have,” said Jon Mark Hirshon, MD, PhD, MPH, professor in the Department of Emergency Medicine at the University of Maryland School of Medicine; member of the Board of Directors of the American College of Emergency Physicians Board of Directors; and co-chair of the Emergency Department Sickle Cell Care Collaborative.

Many of the behaviors physicians are taught to view as “red flags” do not necessarily apply to patients with SCD.

For example, Dr. Kavanagh recalled that she was told in medical school that a patient who comes in asking for a specific medication at a specific dose may be an addict. “But people with SCD are educated about what medication works for them and at what dose, because they have needed these medications most of their lives,” she said.

Racial stereotypes can further stigmatize people with SCD. Dr. Clauw admitted that, during his residency, he often would not believe the descriptions of pain in that patient population for three reasons.

“I thought they were faking because I did not know about opioid-induced hyperplasia, or the biologic mechanisms that allow the brain to ‘turn up the volume’ on the nerves throughout the body.”

—Daniel Clauw, MD

“First, because I was white and they were black and that created a tension with respect to unconscious bias. Second, the pain they exhibited was almost unbelievable.” He recalled seeing patients who would scream out simply from having a bed sheet put over their legs.

The third reason was that, at the time, he did not fully understand their pain. “I thought they were faking because I did not know about opioid-induced hyperplasia, or the biologic mechanisms that allow the brain to ‘turn up the volume’ on the nerves throughout the body,” he said.

Minimizing Misuse

The legitimacy of their pain does not mean that patients with SCD or cancer are immune to opioid addiction.

“Years ago, the concept was propagated that the risks of opioid addiction were lower if one was treating ‘true’ pain, but that has not been biologically proven,” Dr. Brandow said, adding that “the rate of addiction in patients with SCD is no higher than that of other populations.”

A recent study showed that use of opioid prescriptions was more common in cancer survivors than in individuals without a history of cancer, even 10 or more years after a cancer diagnosis.9

Commenting on the results of that study, a co-author said that physicians providing primary care to cancer survivors should question the reasons for long-term, continued opioid use to differentiate between ongoing chronic pain and dependency. (For more advice on mitigating the risk of opioid abuse and misuse among patients with cancer or SCD, see the SIDEBAR.)

Many states require clinicians to review their state’s prescription drug monitoring programs to determine how many opioid prescriptions have been filled by a particular patient in the past 30 days, who prescribed the drugs, what dosage and type were prescribed, and other information.

“Every time we prescribe an opioid at the Medical College of Wisconsin, we are required to look in our database to see the patient’s history, if they have obtained opioids, by whom, and how much,” Dr. Brandow said. “If I find out that a patient has been to multiple EDs between that day and our last visit, it does not automatically mean he or she is an addict. But having this information allows me to ask why he or she is seeking care elsewhere and how we can return to me being the sole provider of their pain medicine.”

Minimizing the risk for abuse will require time and effort from all involved parties, Dr. Hirshon said.

“We need to acknowledge our role and take responsibility to come up with ways to help people,” he said. “We need better patient-provider communication so that we can appropriately support and understand each other.”

There is a delicate balance between protecting people from the harms of opioids and ensuring they get the treatment they need when they are suffering from pain, Dr. Brandow said.

“We can’t ignore this crisis, but it has to be addressed with the right people at the table,” she said. “As legislation and work continue to evolve and address the opioid crisis, it will be important to keep at the forefront the patients who rely on these drugs to decrease their suffering and promote their function.” —By Leah Lawrence


  1.  Centers for Disease Control and Prevention. Opioid Overdose: Understanding the Epidemic. Accessed August 14, 2017, from
  2. Porter J, Jick H. Addiction rare in patients treated with narcotics. N Engl J Med. 1980;302:123.
  3. U.S. Food and Drug Administration’s Center for Drug Evaluation and Research. Memorandum from the FDA Center for Drug Evaluation and Research’s Division of Anesthesia, Analgesia, and Rheumatology Products. November 10, 2008. Accessed August 28, 2017, from
  4. The Joint Commission on Accreditation of Healthcare Organizations. Pain assessment and management standards for hospitals, August 1999.
  5. Leung PTM, Macdonald EM, Dhalla IA, Juurlink DN. A 1980 letter on the risk of opioid addiction. N Engl J Med.2017;376:2194-5.
  6. U.S. Food and Drug Administration. Califf, FDA top officials call for sweeping review of agency opioids policies. Accessed August 14, 2017, from
  7. U.S. Food and Drug Administration. FDA requests removal of Opana ER for risks related to abuse. Accessed August 15, 2017, from
  8. Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain — United States, 2016. MMWR Recomm Rep. 2016;65(No. RR-1):1-49.
  9. Sutradhar R, Lokku A, Barbera L. Cancer survivorship and opioid prescribing rates: a population-based matched cohort study among individuals with and without a prior history of cancer. Cancer. 2017 August 7. [Epub ahead of print]

The Complicated Case of Pain Management and Cancer

Weighing the benefits of using opioids to treat cancer-related pain against the risk of abuse is an ongoing challenge in the hematology/oncology community. Douglas E. Brandoff, MD, director of opioid safety and compliance at Dana-Farber Cancer Institute, helps to manage challenging pain-management cases. Together with a host of fellow physicians, he spoke to Massachusetts legislators in 2016 about the topic.

“We strive to find a balance when caring for our patients with pain. On the one hand, we want to ensure that access to opioid medications is preserved for when clinically appropriate and necessary for treating cancer-related pain,” he said. “[But] we need to be thoughtful about how much we prescribe, and, when appropriate, to try non-opioid pain medications first without automatically turning to opioid therapy.”

To help clinicians limit the opportunities for opioid misuse and abuse when treating patients with cancer-related pain, Dr. Brandoff offers the following advice:

  • Use opioid medication agreements: These agreements between providers and patients allow clinicians to request urine samples and conduct other monitoring measures in patients who are prescribed opioids. This is a universal precaution taken whether or not there is evidence of misuse.
  • Check prescription monitoring programs: Clinicians should thoroughly review their state’s prescription drug monitoring program when prescribing opioids. Such reviews provide valuable information on who is writing a patient’s opioid prescriptions and dispensing medications.
  • Consider non-opioid pain management: Patients may benefit from non-opioid pain-management methods such as palliative radiation, interventional pain management with nerve block or epidural-based steroid injections, neuropathic pain medications, massage therapy, physical therapy, general exercise, Reiki therapy, or acupuncture.
  • Use multidisciplinary care: Clinicians can consult other oncologists or palliative pharmacists to ensure that pain medication will not cause adverse reactions and side effects when combined with certain cancer treatment protocols.

“Ultimately, our goal is to craft a mosaic of therapeutic options: to call upon non-opioid therapies to the fullest extent possible, to safely prescribe opioids when clinically appropriate, to advocate for preserved access to opioids for cancer pain management, and to identify opportunities to taper medication doses when clinically feasible,” Dr. Brandoff said.

Source: Dana-Farber Cancer Institute, Pain Management and Cancer: What You Need to Know.