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13 Articles in Volume 11, Issue #5
Case Study: Patient With Fibromyalgia And Sleep Apnea
Current Treatments for Phantom Limb Pain
Doctor Shopping
Effective Protocol for the Management of Plantar Fasciitis
Giving Severe and Chronic Pain a Name: Maldynia
Is the New Pain Vocabulary Helping Patient Care?
Medications for Chronic Pain—Other Agents
New Technique Combines Electrical Currents and Local Anesthetic for Pain Management
Pain Management Dilemmas of Sickle Cell Disease
Sleep Apnea in Patients With Fibromyalgia: A Growing Concern
The Essential FDA/PDR Indications and Warnings For Opioid Prescribing
The Role of the Clinician In Determining Disability and Pain
Why Does Acute Postoperative Pain Become Chronic and Can It Be Prevented?

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.

The Physicians’ Desk Reference (PDR) has traditionally been a compendium of commercial prescription drug prescribing information. Throw away this notion with regard to opioids. The new indications in the PDR for opioids now carry the highest mandate for prescribing this class of drugs to patients.1 To emphasize the critical nature of the “new PDR,” in recent years the PDR began to carry a US FDA letter to physicians on the inside of its front cover.

To make a point, I recently assisted an attorney who was defending a physician in court for allegedly causing an overdose death with long-acting oxycodone, an opioid-containing combination product, and a benzodiazepine. Out of earshot, he asked me this question: “How come MDs never bother to read the PDR until they are sued?” He admonished me to pass on the ugly tidbit that the first thing a plaintiff attorney does in an adverse drug prescribing case is read the drug’s indication in the PDR. Enough said.

There are two major reasons for knowing the precise PDR indications for opioids. First, several million patients now regularly use opioids for ambulatory pain care. In fact, hydrocodone-containing combination drugs are now the number-one prescribed drugs in the world, replacing former front-runners such as antibiotics, antidepressants, and cholesterol-lowering agents. Second, opioid overdose deaths are now the second most common cause of accidental death, falling behind only motor vehicle accidents.2,3 What’s more, it is clear that a significant number of those deaths resulted from prescribing opioids for other than the indications listed in the PDR.2,3

Just What Is the PDR?

As noted, the PDR is a compilation of “package inserts,” which are the documents of a commercial manufacturer’s product information that is shipped with the product. Be clearly advised, however, that package inserts, particularly the indications, must be reviewed and approved by the FDA. Be fully cognizant, therefore, that the PDR listing for each opioid is a joint, collaborative effort by the private pharmaceutical manufacturer and the FDA.

Although each package insert/PDR listing attempts to provide patient safety information and give the physician prescriber the “how-tos,” there is now another goal. That other goal, aside from providing scientific information, is to shift all legal, not just medical, responsibility away from the manufacturer and federal government directly onto the shoulders of the prescribing physician.

Many organizations, including federal and state medical boards, recently have published guidelines or standards for opioid prescribing. However, these guidelines all pale by comparison to the FDA/PDR indications. So specific and profound is this shift that marketing personnel, including local drug representatives and “dinner speakers,” are trying to stay “on-label.”

Insurance companies have also caught the prevailing winds and will hardly pay for an opioid that doesn’t meet FDA/PDR indications. Although much of the “new order” regarding FDA/PDR indications appears overly restrictive, there is a positive side. If a prescribing practitioner knows the FDA/PDR indications and documents those indications in the patient’s chart, there is great flexibility in prescribing and relative immunity to malpractice or regulatory claims.

FDA/PDR Severity Index

Fundamentally, the FDA/PDR indications for opioid prescribing follow a severity scale or index of five gradations, on which the weakest opioids are prescribed for the simplest, mildest forms of pain and the strongest, most potent opioids are reserved for the most complex, severe pain cases. The index generally indicates that Schedule III opioids under the US Controlled Substance Act are for the milder cases and Schedule II opioids are reserved for the severest cases. The index starts with “mild to moderate” and moves upward to “moderate to severe.” Tables 1 and 2 provide some recommendations regarding FDA/PDR definitions, as well as brief descriptions of each indication.


In addition to indications for each opioid, the FDA/PDR includes an enormous amount of warnings—so many that no practitioner could possibly recall them all. The warning sections cover dosages, frequencies, storage, genetic defects, concomitant diseases, drug abuse, and drug interactions, among others. The extraordinary list of warnings is obviously intended to protect patients but also to deflect all liability away from the manufacturer and FDA and onto the physician should any side effect, overdose, abuse, diversion, or death occur. Only some of the major warnings are given here, because a complete list of FDA/PDR warnings on opioids is now so voluminous that space and memory won’t allow it (see Table 3).


Mild to Moderate Pain

The first gradation or level of the FDA/PDR severity index is listed for codeine compounds and tramadol (Ultram) (see Table 2). The indication for these weak opioids is for “relief of mild to moderate pain.” At no place in the severity index does the FDA/PDR define mild, moderate, or severe pain, and the FDA/PDR leaves it up to the practicing physician to define, describe, and record justification for an opioid.

Moderate to Moderately Severe Pain

The second or higher gradation in the severity index has a subtle step up in indication. Rather than “mild to moderate pain,” this indication is for “relief of moderate to moderately severe pain.” The opioids recommended for this indication are the hydrocodone and oxycodone compounds (eg, Lortab, Norco, Percocet, Vicodin, Vicoprofen, Zydone). These opioids usually are combined with acetaminophen, ibuprofen, or aspirin (see Table 2).

Moderate to Severe Pain When an Opioid Is Appropriate

Note that this step up in the FDA/PDR index leaves out the term “moderately severe” and uses only the word “severe.” Also, this indication includes the word “opioid.” Despite what may appear to be a minor change, this indication recognizes that pain severity may require a pure, potent opioid listed in Schedule II of the Controlled Substance Act. Opioids included here are short-acting, immediate-release formulations of morphine, hydromorphone (Dilaudid), oxycodone, oxymorphone (Opana), and tapentadol (Nucynta).

Tapentadol is the newest potent short-acting opioid to be listed in the FDA/PDR. Interestingly, it has the same indication except that, in contrast with the others, the word “acute” is added to the “moderate to severe” pain indication. Also, the FDA/PDR states that it should not be used for patients younger than age 18.

Moderate to Severe Pain for Around-the-clock Analgesia

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.

The indications and warnings given in the FDA/PDR appear reasonable and appropriate given the epidemic of opioid diversion and overdose deaths that has occurred because of nonindication prescribing.2,3 If a practitioner wishes to prescribe any long-acting opioid, it is highly recommend that the indications for transdermal fentanyl be used as the model and guideline.

Last updated on: September 20, 2011
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