imageShould the reins be tightened on the use of long-term opioid therapy for patients with chronic noncancer pain (CNCP)?

That question is at the heart of a controversy that has boiled over since July when 37 physicians in pain management, public health, psychiatry and other specialties issued a citizen petition calling on the FDA to require opioid label changes that would strike the word “moderate” from CNCP opioid treatment indications and limit the drug’s use solely to severe pain—and then only for a maximum of 90 days at no more than the equivalent of 100 mg of morphine daily.

The petition from Physicians for Responsible Opioid Prescribing (PROP) cited growing U.S. rates of opioid addiction and overdose deaths along with what it said was a lack of evidence for the safety and effectiveness of long-term opioid use for CNCP as the main reasons for the group’s action.

“Unfortunately,” the petition stated, “many clinicians are under the false impression that chronic opioid therapy is an evidence-based treatment for chronic non-cancer pain and that dose-related toxicities can be avoided by slow upward titration. These misperceptions lead to overprescribing and high dose prescribing.”

Pharmacists and physicians opposed to PROP’s proposed label restrictions were quick to respond. Professionals for Rational Opioid Monitoring and Pharmacotherapy (PROMPT), a multidisciplinary group of 35 physicians, pharmacists and other pain specialists, sent a letter to the FDA expressing its own concerns about the safety of chronic opioid use but suggesting an alternative approach emphasizing “clinician education, proactive risk stratification and appropriate therapeutic monitoring.”

PROMPT also endorsed the lengthier and more heated response from the American Academy of Pain Medicine, which called the PROP proposals “seriously flawed, potentially harmful to patients with debilitating pain conditions for whom opioid therapy is indicated, and without substantive scientific foundation.”

Pharmacy Practice News talked with the principals of both PROP and PROMPT and found a depth of conviction on the issue from both sides.

PROP’s Dr. Kolodny: More Opioid Oversight Needed

Andrew Kolodny, MD

Andrew Kolodny, MD, the president of PROP and the chairman of the Department of Psychiatry at Maimonides Medical Center, in New York City, spoke about a decade of rising addiction and overdose death rates “fueled by overprescribing of opioids” mostly for “people with a diagnosis of chronic noncancer pain.”

“What caused this increase,” he said, “was a very effective marketing and education campaign to convince doctors that we were underutilizing opioids.” Physicians were “incorrectly” told, he said, that “we didn’t have to worry about getting patients addicted and that opioids were effective.

“This increase in prescribing,” he added, “has led to this public health crisis. We think it’s now time for the FDA to communicate clearly to the medical community that long-term use of opioids for chronic noncancer pain has not been proven safe and effective.”

According to Dr. Kolodny, “the best available evidence does not suggest that they’re safe and effective. In the United States, where we’re consuming a large portion of the world’s opioid supply, there’s absolutely no evidence that we’re doing any better a job of treating chronic pain than in countries where opioids are prescribed more cautiously.

“In fact,” he added, “the best available epidemiologic data that’s looked at this question comes from Denmark. What they found in a very large study [Pain 2006;125:172-179] was that people who are on opioids long-term for chronic pain were doing very poorly compared with people who were having their pain treated with nonopioid analgesics. There are other studies from the United States that have replicated that.”

He added: “So I don’t believe a reduction in prescribing of opioids for chronic pain will worsen the problem of untreated chronic pain. In fact, because I don’t believe that opioids are effective for most people with chronic pain, I think it exacerbates the problem of untreated chronic pain and to some extent we’re undertreating pain by overprescribing opioids.”

PROMPT’s Dr. Fudin: More Rational Solution Needed

Jeffrey Fudin, PharmD, FCCP

Jeffrey Fudin, PharmD, FCCP, a diplomate of the American Academy of Pain Management and chairman of PROMPT and an adjunct associate professor of pharmacy practice and pain management at Albany College of Pharmacy and Health Sciences, in New York, offered a number of objections to PROP’s proposals. First, he said, it was “absurd” of PROP to ignore the multiplicity of therapeutic options required to treat all of the “unique disorders” that cause CNCP. Moreover, he said, “a lot of patients [with chronic pain] can’t take [other] analgesics for one reason or other.”

Also, limiting opioid dosages to the equivalent of 100 mg of morphine per day disregards the variability in conversion calculations that can occur among different opioid products. He pointed to one study of accepted conversion charts that showed variations in calculations ranging “all the way from –50% to +245%.” (Shaw KC. Eastern States Residency Conference 2012:Abstract 15v).

As for adverse events associated with chronic analgesic treatment, Dr. Fudin said many more are linked to nonsteroidal anti-inflammatory drugs than to opioids, including bleeding disorders, kidney dysfunction and deaths. He also said that most opioid deaths occur in patients on multiple sedating medications (including alcohol) and in those abusing multiple medications, not in patients being treated by knowledgeable pain management clinicians with opioids taken as prescribed.

Moreover, he noted that the largest contributor to rising opioid mortality rates was methadone. A recent report by the Centers for Disease Control and Prevention, he said, found that although 2% of all opioid prescriptions are written for methadone, 33% of opioid-related deaths involve the synthetic opioid (MMWR 2012;61:493-497; Figure). “That’s huge,” Dr. Fudin said. “Methadone pharmacokinetics are very complex, and a lot of prescribers don’t have experience and should not be prescribing it.”

Figure. Drug-related deaths involving opioids by drug type.

A clear example of this, he noted, was seen in the state of Washington, where “the state’s decision to list methadone as a preferred painkiller to cut costs contributed to increasing numbers of overdoses among patients covered by Medicaid” (JAMA 2012;8:749-750).

So what is the answer to the problems that PROP is addressing?

Dr. Fudin believes FDA’s risk evaluation and mitigation strategy (REMS) program for extended-release opioids “is a step in the right direction,” but regulations “should go further and make education mandatory for all people who prescribe opioids.

“It doesn’t matter if [the opioids] are extended-release or not,” he continued. “[Prescribers] need to learn about risk stratification, and they need to be trained in how to do urine drug screens and how to interpret them. They also need to know that if the urine screen shows something unusual, they have to take the next step to order a qualitative confirmation or perhaps follow up with a [serum analysis], and they need to know how to evaluate those serums.”

If prescribers had that knowledge, he said, “outcomes would be much better.”

The PROP proposal is on the FDA docket, and the agency has until January 2013 to respond. Dr. Kolodny noted that even if the agency decided to require label changes, individual physicians would not be restricted from prescribing off-label for longer-term opioid therapy at higher doses for patients with CNCP. “The FDA doesn’t regulate the practice of medicine. It regulates drug companies,” he said.


Dr. Fudin said that although physicians would be able to prescribe off-label, the presence of label restrictions could dissuade many from doing so because of liability concerns, thus denying relief to patients needing more potent analgesics. Additionally, he said, many health insurers including Medicare and Medicaid likely would withhold payments for opioid prescriptions not adhering to label indications—a potential financial hardship for people unable to work because of painful disabilities.

He cited Florida’s experience with the so-called “pill mill” legislation. The new law, he said, is causing many doctors to fear prescribing opioids and pharmacies to be unwilling to fill prescriptions, leaving many elderly patients with chronic pain syndromes not only in pain but also going through withdrawal. “If Florida represents even a small percentage of what we can expect countrywide from the PROP petition, it will be a disaster.”

Dr. Kolodny said the assertion that medical insurers would withhold payments from physicians prescribing opioid therapy off-label was “just plain wrong,” adding that psychiatrists like himself “do a lot of prescribing for off-label indications” and encounter no payment problems with Medicare and Medicaid or other insurers. He also maintained that the reluctance of many legitimate retail pharmacies in Florida and other states to fill prescriptions for opioids like oxycodone was due not to state laws seeking to curb illicit “pill mills,” but to their fear of robberies and because “they just don’t want to be caught in the middle of all this.”

—Bruce Buckley

Two More Pharmacists in Favor of PROMPT

James B. Ray, PharmD, CPE
Pharmacy Clinical Coordinator, Pain and Palliative Care
University of Virginia Health System
Charlottesville, Virginia
Co-chair, Pharmacotherapy Special Interest Group
American Pain Society

We agree with the PROMPT position and that of the American Academy of Pain Medicine, which opposes many of PROP’s goals to regulate the prescribing of opioid medications. Having said that, like the folks who created the PROP petition, I too am very concerned about the increase in prescription drug abuse and overdose deaths. But I do not see that their request to the FDA for limits on opioid prescribing (some via labeling changes) will do anything to significantly curb the misuse and abuse of these medications; rather, the PROP position further polarizes views on these difficult issues.

This debate is certainly an important one, given the prevalence of chronic pain in the United States. Prescribing practitioners will probably see more patients with some type of chronic pain syndrome than any other disease in their professional career. In fact, there are more chronic pain patients in this country than patients with cardiovascular disease, cancer and AIDS combined. However, there is little to no attention being paid to training clinicians on the proper and safe use of opioids for these often complex pain patients (J Pain 2011;12:1199-1208).

As poor as education on pain management is, addiction medicine training is even worse. The diseases of pain and addiction now overlap with each other more and more each day and practitioners are ill prepared to deal with patients with pain and addiction.

For those already practicing, mandatory education programs on safe and appropriate prescribing should be designed and implemented. Those safe practices should include conducting a pain assessment; performing a risk stratification for opioid use; designing a treatment and monitoring plan that includes how to use abuse- and diversion-deterrent tools such as urine drug monitoring; state prescription monitoring programs to assess compliance/development of opioid-related problems; and finally, assessment of function (use of the four A’s) to determine if a continuation of the “trial of an opioid” is warranted.

Additionally, curricula need to be overhauled in all professional health care programs regarding pain management and addiction medicine. Integration into the students’ early experience would create “muscle memory” about how they should treat pain and monitor for abuse and addiction properly once they are in practice. This is especially important in the primary care area of practice.

Dr. Kolodny is right in stating, “The FDA doesn’t regulate the practice of medicine.” Why, then, is PROP asking the FDA to implement these labeling changes? If approved, I fear that the revised labeling will do little to nothing to improve the very problem PROP’s proponents hope to improve. Instead, we need to ask Congress to appropriate money to implement the Institute of Medicine’s recommendations regarding pain management and to create a larger budget within the National Institutes of Health for conducting basic and clinical research on pain and addiction.

As far as what pharmacists can do in all of this, I would suggest that all pharmacists—not just those in our profession who specialize in pain—can and should play a crucial role to ensure safe and proper use of opioids. Specifically, we should be counseling each and every patient about opioids, discussing side effects, including the risk for respiratory depression (especially when opioids are combined with other central nervous system–active agents), stressing that the use of the drug is limited to them alone and that they have a responsibility to secure the medication in their home so no one else has access to it. (Studies suggest that 70% of prescription drugs that are being abused/misused come from friends or family members.)

Moreover, pharmacists should partner with prescribers to advocate for useful electronic prescription monitoring programs in their individual states so that the technology can be added to other tools they already have for effective patient monitoring. Pharmacists also need to advocate for their prescribing colleagues’ right to prescribe judicious quantities of opioids—especially for acute pain problems. And pharmacists can advocate for frequent prescription “take-back” programs in their communities and work with legislators and regulators in their respective state to remove barriers to make this easier for our patients and their families.

In short, I am confident that these measures are a more effective strategy for improving the safety of opioid prescribing than the labeling changes and other heavy-handed prescribing limits sought by the PROP proposal. If you share my concerns, I urge you to make your voices heard by submitting a letter to the FDA during this open comment period (​#!documentDetail;​D=FDA-2012-​P-0818-0001), because if instituted by the FDA, these proposed label changes will only make our lives as clinicians much more difficult and will negatively impact the quality of pain care that we provide to our patients.

Sean Ustic, PharmD
Clinical Coordinator
Pain Management Specialist
South Florida Baptist Hospital
Plant City, Florida
Co-chair, Pharmacotherapy Special Interest Group
American Pain Society

I agree with Dr. Ray: The whole culture of pain needs an overhaul. Most of us in the health care profession are taught only a brief introduction on initiating medications for the treatment of acute or chronic pain. More education on de-escalation and goal setting up front tends to help patients stay engaged in their own recovery of functionality. Opioids continue to be used because they are relatively cheap and effective but likely are not the best option for everyone with chronic noncancer pain. In addition, there aren’t many safe and effective long-term alternatives for chronic noncancer pain. If opioids are not the answer, what is?

With more education, pharmacist-coordinated medication therapy management for patients with chronic pain is an opportunity that hasn’t yet been well recognized. Pharmacists trained in pain management also would be able to help maximize multimodal therapy (nonopioid options), minimize drug–drug and drug–disease state interactions, help interpret drug screens and also aid in goal setting with patients.