Extent of Variability in Fentanyl Plasma Levels During Steady‐State Transdermal Delivery in Older Nursing Home Residents
Year: 2012
Type: article
Abstract: To the Editor: Transdermal fentanyl (TDF) has been increasingly prescribed for older adults in nursing homes (NHs) with persistent pain.1 It provides an important option for people who have difficulty taking oral medications or who have not tolerated oral therapies,2 but the vast majority of data about the pharmacology of TDF have been derived from dissimilar populations in whom pharmacokinetics may differ. NH residents are typically older, thinner, more medically complex, and taking more concomitant medications than traditional study samples. TDF is first absorbed into a fat depot in the dermis before being dispersed throughout the body.2 Less subcutaneous tissue at advanced age might adversely affect TDF deposition. Conversely, mobility-impaired persons may spend more time in positions that create heat or compromise the skin in the area of the patch, increasing TDF absorption.3 A newer matrix delivery system differs from the original reservoir delivery system; their bioequivalence has been reported largely in young, healthy volunteers.4, 5 The authors of the current letter are not aware of any studies that have reported plasma fentanyl levels in NH residents using either TDF delivery system. This study sought to characterize variability in fentanyl plasma levels and simultaneous pain ratings in older NH residents with noncancer pain during a period of stable dosing, during which drug levels should be at steady state. NH residents who were receiving TDF were identified, and they or a proxy provided informed consent. Information on age, body mass index (BMI), indication for TDF use, TDF dose and delivery system, and concomitant medication use was obtained from the medical record. Persons with any change in TDF dose in the prior 30 days were excluded, as were those using as-needed oral fentanyl lozenges and those taking concomitant medications known to interact with fentanyl.6 Blood was then drawn three times from each subject, with each sample being obtained on the second day of a 72-hours TDF dosing cycle. A “right now” pain rating was obtained just before phlebotomy using a 10-point visual analog pain scale.7 Fentanyl samples were processed, frozen, and assayed in a single batch using a fully validated liquid chromatography–tandem mass spectrometry method based on a previous report.8 The ratio of the highest fentanyl plasma level to the lowest level was calculated to characterize the range of variability in drug concentration. The University of Kansas human subjects committee approved the project. Three women and two men aged 81 to 90 participated. All were receiving TDF for persistent noncancer musculoskeletal pain. Table 1 shows TDF dose and delivery system, fentanyl levels, and pain ratings. Participants A through D each demonstrated less than a twofold difference between their highest and lowest fentanyl levels. Participant E's first blood draw showed a remarkably lower plasma level of fentanyl than observed in their other two samples. If this single outlier is disregarded, Participant E's level of variability was similar to that of the other samples. No pattern of association was evident between pain ratings, plasma levels, or variability in plasma levels across samples. Most pharmacological data about TDF are from populations with poor generalizability to older NH residents. A general rule of thumb from drug interaction studies is that variability in drug levels is acceptable when it does not exceed a twofold change (a halving or a doubling of drug level).9 If this rule of thumb is applied to this small pilot sample, fentanyl plasma concentrations remained generally stable in four of five participants. The small sample size is an important limitation, and results should be viewed with caution. The reason for Participant E's outlying result on the first sample is not known. At the time of each blood draw, TDF patches were checked for adherence, exposure to heat, compromised skin, dose, and timing of the last patch change; none of these factors were altered at the time this sample was obtained, but this individual had a BMI of only 14 kg/m2, with correspondingly little subcutaneous fat. In individuals with cancer, cachexia is associated with impaired TDF absorption.10 Consistent drug delivery is imperative if chronic opioid treatments are to be used safely in NH residents. Such persons are highly susceptible to adverse drug effects, and those with cognitive impairment may be unable to self-report changing symptoms if drug delivery is erratic. This is particularly important for drugs with a long half-life with extended dosing intervals. Prescribers should expect manufacturers to provide kinetic data that are realistically generalizable to this most vulnerable group of older adults before widespread adoption of new opioid therapies. Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper. The Research Institute of the University of Kansas Medical Center provided the funding for this pilot study. Author Contributions: Rigler: Study concept and design, analysis and interpretation of data, manuscript preparation. Wiggins: Study design, acquisition of subjects and data, interpretation of data, manuscript preparation. Mahnken: Analysis and interpretation of data, manuscript preparation. Reed: Study design, laboratory testing of samples, interpretation of data, manuscript preparation. Sponsor's Role: The Research Institute of the University of Kansas Medical Center had no role in the study design, conduct of the study, analysis and interpretation, or decision to publish.
Institution: University of Kansas Medical Center
Language: English
Subfield: Anesthesiology and Pain Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2055846149