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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 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

Last updated on: September 20, 2011
First published on: June 1, 2011