The recent request by the US Food and Drug Administration (FDA) to remove the extended-release opioid analgesic Palladone (hydromorphone hydrochloride) from the market,¹ coupled with an FDA advisory report citing fatalities associated with the use of the transdermal fentanyl patch,² may further fuel physicians' fears about prescribing adequate doses of opiates and other narcotic analgesics in the management of acute and persistent pain.

The FDA asked Purdue Pharma LP, the manufacturer of Palladone, to withdraw the medication following the release of additional data that suggest that alcohol combined with the once-daily opiate agent leads to dose-dumping, ie, the rapid release into the bloodstream of the active ingredient from an extended-release product. Dose dumping of Palladone at the lowest marketed dose (12 mg) could lead to serious, or even fatal, adverse events in some patients, and the risk is even greater with higher doses, the FDA stated. Purdue Pharma promptly agreed to suspend all sales and marketing of Palladone in the US pending further discussions with the FDA.

"The news of serious adverse events with Palladone and the fentanyl patch is very sobering, and is likely to limit the willingness of some non-pain specialists to become involved in the regular prescription of long-acting potent opiates," says Charles Argoff, MD, director of the Cohn Pain Management Center at North Shore University Hospital in Manhasset, New York. An abnormal and persistent fear of prescribing pain medication is often referred to as opiophobia.

"No medication class is free of adverse effects, but historically, doctors have been brought up to be very concerned about prescribing opioids," Dr. Argoff tells CIAOMed. "This concern has persisted despite the fact that there are extremely effective forms of analgesics for numerous painful conditions." Legitimate concerns include serious adverse effects such as respiratory depression, addiction, withdrawal symptoms upon cessation, and diversion, he says.

More than 50 million Americans suffer from chronic pain, and nearly 25 million experience acute pain each year as a result of injury or surgery, according to statistics compiled by the American Pain Foundation in Baltimore, Maryland. Moreover, only one in four pain patients receive adequate pain relief.

The current labeling for Palladone, approved in September 2004, already includes the standard opioid warning against the use of these agents in combination with alcohol, but the FDA does not believe that the risk of adverse events can be effectively addressed with prominent labeling and a risk-management plan.

"All powerful pain-management drugs have serious risks if used incorrectly, but the current formulation of Palladone presents an unacceptably high level of patient risk," declared Steven Galson, MD, MPH, acting director of the FDA's Center for Drug Evaluation and Research in Rockville, Maryland, in a written statement. "Although we have not received reports of serious problems, this product has so far been used in a relatively small number of patients. We are concerned that as more patients take this drug, safety problems will arise, since even having one alcoholic drink could have fatal implications."

The recent decision to pull the drug was based on postmarketing pharmacokinetic studies conducted by Purdue. An FDA spokesperson tells CIAOMed that the "Center for Drug Evaluation and Research concluded that had it been aware of the alcohol interaction prior to approval, Palladone would not have been approved, and reformulation to address this safety concern would have been required."

Along with the requested withdrawal of Palladone, the FDA is evaluating the potential effects of alcohol on other sustained-release opiates, and has already conducted in vitro testing on the currently marketed products. Based on the results of those tests, the FDA has requested that certain companies conduct in vivo studies to determine whether, and to what extent, an interaction with alcohol may occur. "Once the data from these studies become available, the FDA will be able to determine the magnitude of any potential risk from an alcohol interaction and take appropriate action to manage that risk," the FDA spokesperson says. "Current labeling for the extended-release opiates already includes a warning against concomitant use with alcohol, and the FDA is working with sponsors to further strengthen these warnings while we await more definitive data."

"I would hope this issue does not have any impact on the appropriate use of opioids in pain management, as we still have a number of opioids with a long history of safe and efficacious use in chronic pain and cancer pain," says John Clark, MD, medical director of the Calgary Health Region Chronic Pain Center in Alberta, Canada. "Any negative information can fuel opiophobia, but this is often through lack of understanding or knowledge, and consequently poor pain management." Palladone is not marketed in Canada.

Advisory issued on the safe use of fentanyl

FDA officials have also warned that the fentanyl patch may trigger a drug overdose, following reports of 120 fatalities that may be associated with the patch. Deaths and overdoses have occurred in both the generic and the brand name (Duragesic) patch.

The fentanyl patch is designed for patients who are able to tolerate narcotics analgesics and are in need of round-the-clock pain management that cannot be provided by other drugs. In a written statement, FDA officials emphasized that there was no conclusive link between the deaths and overdoses and the patch. The fentanyl patch has been on the market for 15 years.

Physicians must be committed to proper monitoring of their patients

"Some of the issues about inappropriate use of opioids are real, and we shouldn't hide our heads in the sand," Dr. Argoff says. "Clearly, physicians who prescribe opioids on a long-term or chronic basis need to really be committed to proper follow-up, monitoring, and screening of patients to make sure [the drugs] are not being misused.

"One of the beautiful things about being in pain management is that it emphasizes the need for good old-fashioned medicine," he says, meaning, "we must take a history, perform a physical exam, assess the etiology of the problem, do appropriate diagnostic studies, treat patients based on information available at the time, and follow up and re-assess."

According to Dr. Argoff, the recent government actions against physicians for prescribing opiates-even those who kept meticulous records and signed patient-treatment agreements/opiate contracts-will likely deter many others from prescribing these agents in the future. "Many increasingly see that there seems to be too much risk in prescribing opiates, and no protection at all from the [Drug Enforcement Administration]," he says.

"Unfortunately for all of us who can be patients, this will fuel the fear, but at the same time, things have a way of [balancing out]," Dr. Argoff observes. "The time is now to better educate physicians and patients about the treatments that are available to them. To be most effective, such education needs to start in medical school."

References:

1. FDA asks Purdue Pharma to withdraw Palladone for safety reasons [press release]. Bethesda, Md: Food and Drug Administration; July 13, 2005.
2. FDA issues public health advisory on the fentanyl patch [press release]. Bethesda, Md: Food and Drug Administration; July 15, 2005.