New Opioids: Expensive Distractions or Important Additions to Practice?

Abstract

Russell K. Portenoy, M.D.: I have been involved in doing a lot of the studies with the new rapid-onset fentanyl formulations, including the very first one that was on the market, oral transmucosal fentanyl citrate. These formulations have all been developed in response to the view that breakthrough pain is an unmet need largely because the time course of a typical breakthrough pain is much shorter than the timeaction relationship of a typical oral short-acting drug like oxycodone or morphine. The vast majority of breakthrough pain, when evaluated in these epidemiologic studies, last less than 1 hour and have a time to maximum intensity of 10 minutes or less. When you compare that to the time-action relationship of an oral drug like morphine, you can see that there is a mismatch. Oral transmucosal fentanyl was commercially successful. The second formulation, fentanyl buccal citrate, has also been successful for the pharmaceutical company. This success has induced other companies to formulate new products and get them on the market. The Holy Grail with these drugs has been to try to have a time-action relationship that almost approximates an intravenous bolus, with the goal of translating a rapid effect into clinical benefit by addressing the mismatch I mentioned. Interestingly, there has been very, very little research comparing the standard oral agents, like morphine or oxycodone, with any of the rapid-onset fentanyl formulations. Although the very few studies that have been done have had methodological concerns, they have found greater satisfaction and greater pain control with the fentanyl formulations. This cannot be viewed as definitive, however, because of the methodological issues and the need for replication in broader clinical populations and real world settings. Right now on the market we have the oral transmucosal fentanyl citrate, the fentanyl buccal tablet, and the new bioerodible mucoadhesive patch, which just got approved. Coming on the market in relatively short order will be a sublingual dissolvable tablet, intranasal formulations, and possibly aerosolized formulations that will be inhaled. These drugs all will have company-initiated Risk Evaluation and Mitigation Strategies (REMS), which the U.S. Food and Drug Administration has been required by law to put into place. In the case of the patch and with others coming, these REMS programs appear to add some burden to doctors to make sure that they are aware of risks, including drug abuse and unintentional overdose, and the management guidelines to minimize them. Doctors are going to have to get used to the concept of REMS and be willing to spend an extra few minutes to review guidelines, document that they are knowledgeable about the risks, and be entered into a registry. To the extent that REMS affects the newer rapid onset fentanyl formulations before affecting other opioid formulations, they may slow down the uptake of the new products as they come on the market.