Question
Do you know of any controlled studies supporting a 48-hour dosing interval for transdermal fentanyl patches? This seems to have become common practice among pain management specialists, but I have only found anecdotal support for the practice in specific populations (eg, terminal pancreatic cancer patients).

Response from Jeffrey Fudin, BS, PharmD Adjunct Associate Professor, Albany College of Pharmacy/Union University, Albany, New York; Clinical Pharmacy Specialist, Stratten VA Medical Center, Albany, New York

The FDA-approved and recommended dosing interval for transdermal fentanyl is every 72 hours. However, some patients who may require a shorter dosing interval to obtain adequate uninterrupted pain relief, and the literature supports this as a way to achieve the desired continual analgesia. For example, dosing intervals were decreased to 60 hours and 48 hours in certain adult studies; there is no supportive evidence in children or adolescents.^[1-3]

After the transdermal fentanyl patch is applied, the skin absorbs the drug and forms a depot in the upper skin layers. This results in a concentration gradient that drives drug release from the system into the skin at a relatively constant rate. The rate of fentanyl delivery to the skin over the 72-hour application varies among individuals and groups of patients.^[4,5] Once in the skin, the drug is absorbed transdermally via systemic circulation.

The strength of the fentanyl patch is represented as the average amount of drug delivered to the systemic absorbed circulation per hour across "average" skin. Therefore, there is much inter- and intrapatient variability in the pharmacokinetics of fentanyl due to differences in skin integrity, body clearance of fentanyl, and volume of distribution.^[4] Fentanyl is also a very minor substrate of CYP3A4, so inducers or inhibitors of this enzyme could potentially alter the metabolism of the drug as well.^[4,5]

Serum concentrations gradually increase after application, leveling off between 12 and 24 hours, for potentially up to 6 days after initial application. Fentanyl absorption is 47% complete at 24 hours, 88% complete at 48 hours, and 94% complete at 72 hours.^[6] Peak serum concentrations occur between 24 and 72 hours after application. Serum levels begin to decline slightly over the last 24 hours of the 72-hour interval.^[5]

One controlled trial evaluated long-term use of transdermal fentanyl in 51 patients with chronic cancer pain.^[1] Patients were also given oral morphine for breakthrough pain. Physicians could adjust the dosing interval of the fentanyl patches after day 15 if pain relief was inadequate for the entire 72-hour dosing interval. In 12 patients (23.5%), the dosing interval needed to be shortened. In 6 patients, it was reduced to 60 hours, and in another 6, it was reduced to 48 hours. In the 60-hour dosing interval group, 3 of the patients needed a further shortening of the interval to 48 hours. Patients with shortened dosing intervals had more stable pain relief without any severe side effects. However, the 60-hour dosing interval wasn't practical due to the schedule for changing the patch.^[1]

In another controlled trial, 50 patients with gastrointestinal, head, or neck cancer were placed on transdermal fentanyl for chronic pain. Clinicians measured blood pressure, heart rate, respiratory rate, pain intensity, prevalence and intensity of adverse effects, general mood, and doses of rescue morphine taken. All patients were initially placed on a fentanyl dosing interval of 72 hours. During the trial, 18 patients required a reduction in the dosing interval to 48 hours. This occurred when the duration of analgesia was inadequate despite an increase in strength. In no instances did decreasing the dosing interval result in a higher incidence of adverse effects.^[2]

Similarly, a retrospective study assessed the dosing frequency in patients receiving long-acting opioids for various types of pain.^[3] Of the 258 patients in this study, 67 were using transdermal fentanyl for pain, and nearly a quarter of them (23.9%) needed a reduction in the dosing interval to 48 hours for adequate pain relief. Other long-acting opioids included in this study had similar results, including MScontin, Oxycontin, and Kadian. In fact, nearly every patient in this analysis said they perceived end-of-dose failure of analgesia as the reason for taking the medication more frequently.^[3]

For most patients, the 72-hour dosing interval for transdermal fentanyl is appropriate, but a small number do not receive adequate pain relief throughout that dosing period. According to the package insert, if pain relief is inadequate, whether the dose should be increased as opposed to reducing the dosing interval should be assessed. The dosing interval should never be shorter than 48 hours.^[5] However, it is always best to use the least amount of medication to achieve the desired response. In my opinion, the best way to do this with a transdermal system is to keep the dose lower and shorten the dosing interval, not the opposite. Although increasing the area under the curve by raising the dose while maintaining a 72-hour interval is an alternative, it is perhaps a less desirable approach.