Duragesic(R) Transdermal Patch: Postmortem Tissue Distribution of Fentanyl in 25 Cases

Abstract

Fentanyl is a potent, short-acting narcotic analgesic widely used as a surgical anesthetic and for the control of pain when administered in the form of a transdermal patch. The success of the patch can be attributed to fentanyl's low molecular weight and its highly lipophilic nature, which enables it to be readily absorbed through the skin and subsequently distributed throughout the body. Over the past three years, the Los Angeles County Coroner's Toxicology Laboratory has encountered 25 cases involving Duragesic patches (fentanyl), and their postmortem tissue distributions are presented here. The analysis of fentanyl from postmortem specimens (3-mL or g sample size) consisted of an n-butyl chloride basic extraction followed by identification and quantitation on a gas chromatograph-mass spectrometer using the selected ion monitoring (SIM) mode. The fentanyl ions monitored were m/z 245, 146, and 189 and the internal standard, fentanyl-d5 ions, were m/z 250, 151, and 194 (quantitation ion underlined). The linear range of the assay was 1.67 microg/L to 500 microg/L with the limit of quantitation and detection of 1.67 microg/L. The postmortem tissue distribution ranges of fentanyl in the 25 fatalities were as follows: heart blood, 1.8-139 microg/L (23 cases); femoral blood, 3.1-43 microg/L (13 cases); vitreous, +<2.0-20 microg/L (4 cases); liver, 5.8-613 microg/kg (22 cases); bile, 3.5-262 microg/L (15 cases); urine, 2.9-895 microg/L (19 cases); gastric, 0-1200 microg total (17 cases); spleen, 7.8-79 microg/kg (3 cases); kidney, 11 microg/kg (1 case); and lung, 31 microg/kg (1 case). The age of the decedents in this study ranged from 19 to 84, with an average age of 46. The modes of death included 15 accidental, 5 natural, 3 suicidal, and 2 undetermined. The main objectives of this paper are to show the prevalence of fentanyl patches in our community and to aid the forensic toxicologist with the interpretation of postmortem fentanyl levels in casework.

Transdermal fentanyl: Pharmacology and toxicology

“…The mean measured fentanyl blood concentration in 6 transdermal fentanyl fatalities was 21 ng/mL (10-38 ng/mL) [35] In a series of 25 deaths potentially involving transdermal fentanyl, the 8 cases felt to be "clearly not related" had heart blood concentrations of <2-7 ng/mL, while in the 12 cases considered attributable solely to fentanyl the heart blood concentrations ranged from 16 to 139 ng/mL [27]. Postmortem redistribution is considered to be minor, though variable, with a heart/femoral ratio of 1.6 (range 0.7-4.6) noted in a study of 13 transdermal fentanyl device-related fatalities [27].…”

“…Misuse is defined as misguided use for therapeutic purposes, and may be intentional or unintentional. Misuse may be attributed to either the physician or the patient and includes, for example, prescribed use for an acute pain syndrome by an inadequately informed physician or the intentional application of multiple transdermal devices by a patient for enhanced analgesia [2,4,[27][28][29]. In one report a physician, in an attempt to decrease the dose, improperly advocated that his patient cut the transdermal device into quarters before applying it [30].…”

“…Although the latter data are fatality related, they often inadequately distinguish between misuse and abuse, and generally fail to specify the form and/or route by which fentanyl was utilized. A more obvious association from the medical examiner literature is the utilization of the transdermal fentanyl delivery systems as a method of suicide [27,35,36]. While in many cases the cause of death may be confirmed objectively, deciphering the manner of death to determine who died from fentanyl abuse rather than suicide is often difficult.…”

“…However, even determining that fentanyl is the cause of death on the basis of postmortem blood fentanyl concentrations is occasionally fraught with difficulty. For example, as discussed later, pharmacodynamic effects, such as opioid tolerance, and pharmacokinetic effects, such as postmortem redistribution, complicate the interpretation of the postmortem blood concentration [27]. See the Relevant Forensic Toxicology section below for further discussion.…”

Appropriate use of transdermal drug delivery systems

“…The drug in the reservoir can be present in suspension, solution, gel, or a solid polymer matrix state. Reservoir TDDS should not be cut, as altering the integrity of the system could create a dose-dumping effect that can lead to drug toxicity (including death) or inadvertent drug exposure to others [8,9] . Matrix (monolithic) systems contain a similar distribution of drug throughout the patch and exist in several forms including simple matrix systems, drug-in-adhesive system, and multilayer matrix systems [1] .…”