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The Essential FDA/PDR Indications and Warnings For Opioid Prescribing

The Physicians’ Desk Reference should no longer be viewed as interesting bits of information generated by a pharmaceutical company to sell a product. Rather, the indications and warnings are a collaborative effort by the manufacturer and FDA and must be known and followed by prescribers of opioids.
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The precise indication in this step is for slow-release, long-acting opioids. It is a lengthy indication that specifically states “management or relief of moderate to severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time.” The opioids included here are the long-acting formulations of fentanyl (Duragesic), hydromorphone (Exalgo), methadone (Dolophine), morphine (Avinza, Kadian), oxycodone (OxyContin), and oxymorphone (Opana ER). The new, long-acting formulations of buprenorphine transdermal (Butrans) and tramadol (Ryzolt) are included. A minor difference is assigned to tramadol in that its indication is “moderate to moderately severe” pain, recognizing that tramadol is not as potent as the other agents in this category.

The listed indication for transdermal fentanyl (Duragesic) is particularly instructive. In addition to the standard indication, the word “persistent” is added to “moderate to severe chronic pain.” Also, it requires that the pain “cannot be managed by other means, such as nonsteroidal analgesics, opioid combination products, or immediate-release opioids.” Simply put, a long-acting opioid should not be prescribed to patients unless it is added to an existing active, short-acting opioid regimen. Although used only for the fentanyl transdermal package insert, this warning indication should be applied to all long-acting opioid preparations, as the long-acting opioids are a “class” of compounds, and a prudent practitioner should adopt the most descriptive and detailed indication for this class.

Some serious investigation and chart documentation must be done before a long-acting opioid is prescribed. A history must be taken from each patient and documented in the patient’s chart. Five basic but necessary screening questions for patients are listed in Table 4.

Breakthrough Pain in Tolerant Cancer Patients

This is the highest gradation in the FDA/PDR severity index and applies only to buccal or sublingual fentanyl products (Abstral, Actiq, Fentora, Onsolis). The specific indication is “management of breakthrough pain in patients with cancer who are already receiving and who are tolerant to around-the-clock therapy for their underlying persistent cancer pain.” Physicians are encouraged to learn this indication, not just for oral fentanyl specificity but also because it introduces the term “breakthrough pain,” which is an indication now firmly entrenched in pain practice.

The Major Problem: Ill-defined Terms

The major problem with the FDA/PDR indications is that some terms are ill defined. To this end, an attempt is made here to clarify some terms and provide guidelines to meet the required indications.

First, it is left totally up to the practitioner to determine the difference between mild, moderate, moderately severe, and severe pain. There are neither physiologic parameters, such as blood pressure and pulse rates, nor functional parameters, such as interference with activities of daily living, given in the FDA/PDR to guide the practitioner. The terms “around-the-clock,” “persistent,” and “extended period or time” are neither defined nor described. For example, “persistent” is not defined as to whether the pain is chronic and intermittent or chronic and constant. “Around-the-clock” is preceded by the term “continuous,” so it should be assumed that pain relief is required for the 24-hour cycle, including sleep time. This means that a steady-state blood opioid level is needed, even during sleep. The term “extended period” is not defined, but practitioners are highly urged to regard this as reserved for intractable, incurable cases that will last a lifetime. It is clearly worth noting that a major reason for overdose deaths and diversion is that some physicians prescribed long-acting opioids to patients who did not meet the FDA/PDR indication for a long-acting opioid.2,3 The tables give some specific clarifications and suggestions for use of long-acting opioids.

Off-label Use of Opioids

Experienced practitioners know that opioids must sometimes be prescribed other than as indicated in the FDA/PDR. For example, the frequency of administration may vary from that listed. There is no upper dosage limit for opioids. Off-label opioid use is perfectly acceptable, but when an opioid is prescribed off-label, a written off-label consent form should be used. Most important, there needs to be some written chart documentation to justify off-label opioid prescribing.

Should You Restrict Your Opioid Prescribing?

Possibly. The opioid indications in the FDA/PDR are due cause for every practitioner to reflect on whether or not to prescribe opioids from every class or just some opioids. For example, the most critical question is whether you are willing and able in your practice to evaluate the patient, generate the records, and document the requirements to prescribe long-acting opioid drugs. Please review the indication and requirements for transdermal fentanyl (see Table 5). Are you prepared to generate and maintain records to document the indication and monitor around-the-clock dosing, which, in essence, requires a 24-hour steady-state blood level and, in some cases, therapeutic blood monitoring? Are you able to see opioid-treated patients frequently and take the time to prepare documentation to meet the indication?

Practitioners are perfectly justified and even advised in many cases to restrict their prescribing to opioid-combination drugs. These have proved to be remarkably safe and nonabusable compared with the pure opioids. Once you carefully review the FDA/PDR indications, you may come to the conclusion that you will restrict your opioid prescribing and refer those patients with more severe pain to other physicians.


The FDA/PDR indications for opioids must now be taken very seriously by physicians who wish to prescribe opioids. Practitioners can no longer view opioid descriptions in the PDR as interesting bits of information generated by a pharmaceutical company that wishes to sell a product. Indications and warnings as laid out in the FDA/PDR are a collaborative effort by the manufacturer and federal government, and they must be known and followed by prescribers of opioids.

If a clinician is going to use an opioid other than as indicated in the PDR package insert, the patient must be informed and must give off-label consent. Keep in mind that the FDA/PDR not only gives the indication and warnings about opioids, but it also fundamentally transfers legal liability to the prescriber and away from the manufacturer, pharmaceutical distributor, and federal government. Given that the PDR indication and warnings often are the basis of malpractice suits and regulatory prosecutions, prescribers must consider them equal to or more compelling than any regulations or guidelines their respective state or professional organizations may dictate or recommend. In fact, they are complementary to them.

Last updated on: September 20, 2011