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Fentanyl in postmortem forensic toxicology
Abstract
Fentanyl is a powerful opioid used for the induction of anesthesia as well as for the management of severe pain. In recent years, transdermal fentanyl "patches" have become popular for outpatient management of chronic pain. The high potency and outpatient availability of fentanyl has also made it a highly sought-after drug of abuse. Deaths in which fentanyl is detected challenge medical examiners who must decide whether a given case represents therapeutic administration or overdose.
The current review seeks to present data about fentanyl that are relevant to the interpretation of postmortem blood and tissue fentanyl concentrations as well as to highlight areas which can be helpful or misleading in the evaluation of deaths potentially related to fentanyl exposure.
Standard searching of the PubMed database for studies, case series, and case reports involving fentanyl kinetics, chemistry, and postmortem behavior was performed. Search terms typically included "postmortem" and "fentanyl," as well as "kinetics" and "analysis," where appropriate. Additional references were located as citations from reviewed papers or as conference abstracts.
The postmortem behavior of fentanyl is influenced heavily by pH changes and the antemortem kinetic behavior of the drug, especially, by its distribution. Postmortem blood fentanyl concentrations do not correlate directly with antemortem blood concentrations. Without adequate evaluation of kinetic data, investigative information and consideration of postmortem changes, misinterpretation of postmortem fentanyl results is likely.
... It should be noted that kinetic interaction between fentanyl and other drugs because of CYP3A4 inhibition has been the subject of multiple studies [17]. These studies are in line with the concept that fentanyl is a high hepatic extraction drug. ...
... These studies are in line with the concept that fentanyl is a high hepatic extraction drug. That is, the removal of fentanyl from the blood is more dependent on total blood flow through the liver than on the intrinsic activity of the enzymes involved in its metabolism [17]. On the other hand, even if there were a mutation in the CYP3A4 or CYP3A5 that would interfere with the conversion of fentanyl to norfentanyl, the phenotypic difference would still be reflected in the blood fentanyl/norfentanyl ratio. ...
... It is critical that adequate consideration be given to issues including medical history, concomitant medication use, fentanyl tolerance, scene and investigative information, and autopsy findings, along with accurately measured postmortem fentanyl and norfentanyl concentrations. We agree with Dr. Palmer that the greatest peril in the explanation of postmortem fentanyl concentrations lies in overinterpretation of the measurements [17]. ...
... However, there was no mentioning of any measurement for blood or urine norfentanyl concentrations. Numerous independent studies have demonstrated there can be a significant overlap in concentration range between cases where fentanyl was deemed to have played a role in the death (overdose) and those where the finding of fentanyl was considered noncontributory (natural or incidental) [5]. Indeed, it is well known that tolerance to the effects of fentanyl does develop and may be substantial [5]. ...
... Numerous independent studies have demonstrated there can be a significant overlap in concentration range between cases where fentanyl was deemed to have played a role in the death (overdose) and those where the finding of fentanyl was considered noncontributory (natural or incidental) [5]. Indeed, it is well known that tolerance to the effects of fentanyl does develop and may be substantial [5]. Bleeker [6] reported a case of a 58-year-old female with neuropathic pain on a transdermal fentanyl dose of 3,400 lg/h (thirty-four, 100 lg/h patches). ...
... When the patient was admitted to the hospital for inadequate pain relief, a plasma fentanyl concentration of 178 ng/mL was recorded on admission, and the patient was alive and without any symptoms of over-sedation. In this regard, it is obvious that the concept of a ''toxic'' or ''lethal'' dose or an arbitrary drug level has little validity, although occasionally quoted and should be avoided [5]. ...
... Tricyclic antidepressants heart, peripheral [16][17][18] concentrations are a reliable indication of a drug concentration at the time of death. Using fentanyl as a representative case example (12), the biochemical and physical mechanisms responsible for increasing fentanyl concentrations in femoral/peripheral and heart blood over the postmortem interval are complex and likely vary from case to case. Fentanyl is a lipophilic drug, which is highly bound to proteins at physiological pH (7.4). ...
... Fentanyl distribution can be described to occur in a three-compartment model: 1. the circulatory system (blood) plus vessel rich highly perfused tissue (liver, lung, heart) compartment; 2. peripheral compartment comprised of skeletal muscle; and 3. peripheral compartment comprised of adipose (fat) tissue. High partitioning of fentanyl into skeletal muscle occurs rapidly, with tissue concentrations 4-to 10-fold higher than in plasma (12). There is also a high tissue-to-blood concentration gradient for liver, 3-to 35-fold, and heart, 2-to 5.3-fold (11,18,19). ...
... Recently, Anderson and Muto (21) have proposed the similar utilization of liver tissue to differential therapeutic from toxic or fatal fentanyl concentrations. The use of liver concentrations is further supported by the recent observations of fentanyl PMR in PB (11,12). Carefully designed studies need to be performed to better understand the relationship between central and peripheral blood and liver concentrations during the postmortem interval for drugs prone to PMR. ...
... Postmortem concentrations of drugs, primarily in heart blood samples, but also in samples of peripheral blood, cannot be directly compared with therapeutic concentrations in serum determined in vivo (5). In addition to information about the pharmacokinetics, data describing postmortem blood concentrations that can be expected following appropriate therapeutic use are of great value in forensic toxicology (6). ...
... Obviously, there is a considerable overlap in concentration ranges of cases in which fentanyl was determined to have played a role in the death and those in which fentanyl was considered as therapeutic or noncontributory (see Figures 5 and 6). This was also discussed extensively in the review of Palmer (6). Despite our intention and these comprehensive data, determining a threshold level that would enable the discrimination between toxic or nontoxic concentrations of fentanyl is not possible based on our data and various data from the literature. ...
... Additional medication leading to altered pharmacokinetic effects by the inhibition of CYP 3A4 could be another reason for higher fentanyl levels (39). Although most of the studies discovered zero, or minimal, effects of CYP 3A4 inhibitors (6,40,41), Ibrahim et al. concluded that because fentanyl is a high hepatic extraction drug, the removal of the drug from the blood is more dependent on total blood flow though the liver than on the intrinsic activity of the involved enzymes (40). Because most of our patients were critically ill, a modified organ function might be conceivable. ...
In forensic toxicology, several fatal intoxications with fentanyl have occurred in the recent past, but there are rare discussions in the literature of postmortem fentanyl blood concentrations subsequent to lethal and non lethal applications. To study this problem, we analyzed postmortem blood concentrations (vena femoralis) of 118 cases with therapeutic use of fentanyl and compared them with serum levels of 27 living persons after therapeutic administration of fentanyl patches (Durogesic). Basically, blood concentrations in postmortem specimens cannot be directly compared with in vivo serum levels: in our study, we observed that postmortem fentanyl blood concentrations were on average up to nine times higher than in vivo serum levels at the same dose. These differences could be explained by postmortem redistribution, but they were higher than expected on the basis of the physical and chemical properties of fentanyl alone. The special pharmacokinetics of the drug after long term transdermal application seem to play an important role in this phenomenon. In addition, there was no clear correlation between transdermal fentanyl dose and blood or serum concentrations, either antemortem or postmortem. Our study provides extensive data for postmortem peripheral blood concentrations after therapeutic non-fatal fentanyl patch application and demonstrates once more that in forensic toxicology, blood concentrations must be holistically interpreted with respect to all aspects of a case.
... Opioid non-tolerant patients may suffer fatal consequences if the drug is prescribed inappropriately, even with therapeutic intent. 4 Oppliger et al. 1 reported that the post-mortem cardiac blood concentration of 25 ng ml À1 in their case presentation was well above the therapeutic range of 0.3 to 10 ng ml À1 . ...
... Indeed, it is well known that tolerance to the effects of fentanyl does develop and may be substantial. 4 Liappas et al. 5 described a 36-year-old female with non-malignant chronic pain, who resorted to placing transdermal fentanyl patches in her mouth for pain control, claiming this route provided faster and more effective pain relief than application to the skin. Eventually, she was using ten 25 mg h À1 patches/day in this manner over a 15-month period and reported only slight fatigue and somnolence after use. 5 Bleeker 6 reported a similar case of a 58-year-old female with neuropathic pain on a transdermal fentanyl dose of 3400 mg h À1 (34 100 mg h À1 patches). ...
... In this regard, it is obvious that the concept of a 'toxic' or 'lethal' dose or an arbitrary drug level has little validity, although occasionally quoted, and should be avoided. 4 In patients with chronic non-cancer pain with suicidal risk, opioid therapy is considered a relative contraindication. 7 As Oppliger et al. alluded, both depression and chronic pain are independent risk factors for suicide. ...
... Opioid non-tolerant patients may suffer fatal consequences if the drug is prescribed inappropriately, even with therapeutic intent. 4 Oppliger et al. 1 reported that the post-mortem cardiac blood concentration of 25 ng ml À1 in their case presentation was well above the therapeutic range of 0.3 to 10 ng ml À1 . Indeed, it is well known that tolerance to the effects of fentanyl does develop and may be substantial. ...
... Indeed, it is well known that tolerance to the effects of fentanyl does develop and may be substantial. 4 Liappas et al. 5 described a 36-year-old female with non-malignant chronic pain, who resorted to placing transdermal fentanyl patches in her mouth for pain control, claiming this route provided faster and more effective pain relief than application to the skin. Eventually, she was using ten 25 mg h À1 patches/day in this manner over a 15-month period and reported only slight fatigue and somnolence after use. 5 Bleeker 6 reported a similar case of a 58-year-old female with neuropathic pain on a transdermal fentanyl dose of 3400 mg h À1 (34 100 mg h À1 patches). ...
... In this regard, it is obvious that the concept of a 'toxic' or 'lethal' dose or an arbitrary drug level has little validity, although occasionally quoted, and should be avoided. 4 In patients with chronic non-cancer pain with suicidal risk, opioid therapy is considered a relative contraindication. 7 As Oppliger et al. alluded, both depression and chronic pain are independent risk factors for suicide. ...
... In both cases, the release of the drug occurs at a constant rate for 72 hours. [20][21][22][23] After the patch application, serum levels of fentanyl increase gradually and become stable in 12-24 h so fentanyl interactions with sedatives, hypnotics and other opioids are still possible hours after the patch has been removed. [7] After removal of the patch, the absorption continues for approximately 12 hours thanks to the stratum corneum depot thus removal of the patch does not quickly eliminate the risk of fentanyl interactions with other drugs. ...
... [24] The inactive metabolites and less than 10% of the intact molecule, are mainly excreted in urine and faeces. Less than 1% is metabolized by alkyl hydroxylation, N-dealkylation or amide hydrolysis to the inactive compounds hydroxyfentanyl, hydroxynorfentanyl and despropionylfentanyl. [6,7,21,25,26] Minor metabolites such as hydroxypropionyl-fentanyl and hydroxypropionyl-norfentanyl are created through different pathways without relevant pharmacological activity. ...
... Interpretation of postmortem fentanyl concentrations must consider also the possibility of drug tolerance. [11,21] Norfentanyl blood concentration was available only in 7 of the 29 articles. In 4 cases multisite sampling was performed (femoral blood and heart blood), in 5 cases the blood sample was collected from the femoral vein, in 1 case the sample was collected from the heart and in 1 case the source of sampling was not reported. ...
Background
Transdermal fentanyl patches represent an excellent alternative for the treatment of chronic and cancer-related pain, but can lead to death due to their incorrect use or increasing abuse.
Purpose
Present an overview of literature regarding fentanyl patch related fatalities.
Methods
Literature research into PubMed database for all types of publications. Search terms were “fentanyl”, “patch” and “death”. Additional publications by manual examination of references of the PubMed results were included.
Results and Conclusions
To date 29 publications about transdermal fentanyl patch related deaths are available on PubMed and their time span is of 26 years. A total of 674 deaths related to fentanyl were found, 658 associated with transdermal fentanyl patch. Use of patches was more frequently in males (68%) than in females (32%) and in the 31-40 and 41-50 decades. The most frequent route of administration was the transdermal route, followed by oral and intravenous route. Cause of death was in 63.5% of cases drug abuse, followed by accidental death (16.2%), death unrelated to fentanyl (13.3%) and suicide (2.8%). The use of concomitant drugs was reported in 19 of the 29 publications and antidepressant followed by benzodiazepines and ethanol were the most frequent discovered drugs. In conclusion, fentanyl transdermal patch misuse and abuse is a major problem and still need to be completely addressed.
... Using postmortem blood and urine norfentanyl/fentanyl ratios in the investigation of fentanyl-related deaths Sir, Deaths in which fentanyl is detected challenge medical examiners, who must decide whether a given death represents therapeutic administration or was an overdose. [1] Numerous independent studies have demonstrated there can be a significant overlap in concentration range between cases where fentanyl was deemed to have played a role in the death (overdose) and those where the finding of fentanyl was considered noncontributory (natural or incidental). [1] We believe this is especially true when fentanyl is involved along with other drugs, i.e., when one needs to find out, with some degree of certainty, whether acute fentanyl toxicity did occur and caused the death of the patient. ...
... [1] Numerous independent studies have demonstrated there can be a significant overlap in concentration range between cases where fentanyl was deemed to have played a role in the death (overdose) and those where the finding of fentanyl was considered noncontributory (natural or incidental). [1] We believe this is especially true when fentanyl is involved along with other drugs, i.e., when one needs to find out, with some degree of certainty, whether acute fentanyl toxicity did occur and caused the death of the patient. We propose that ratios of postmortem blood and urine norfentanyl/fentanyl may be helpful in predicting the role of fentanyl in patient's death. ...
... Fentanyl is a synthetic phenylpiperidine l-opioid receptor agonist which clinically can be absorbed transmucosally (TM), intravenously (IV), and/or transdermally (TD) (3,4). The present case involves absorption via both TM and TD routes. ...
... Other explanations could be redistribution (25), or collection or laboratory error. There have been case reports of delayed respiratory depression related to sequestration and ion trapping of fentanyl into acidic gastric juice, followed by reabsorption of the unionized form and/or release of drug depots from muscles (4,26) which could have occurred in our patient. Continued absorption is unlikely postmortem (27). ...
Opioid-related mortality happens, even in healthcare settings. We describe serial postmortem fentanyl blood concentrations in a hospital inpatient who fatally abused transdermal fentanyl. This is a single-patient case report. A 42-year-old man with lymphoma was started on transdermal fentanyl therapy while hospitalized for chronic abdominal pain. The patient was last seen awake 1.3 h prior to being found apneic and cyanotic. During the resuscitation attempt, a small square-shaped film was removed from the patient's oropharynx. Femoral blood was collected 0.5 and 2 h postmortem, and the measured fentanyl concentration increased from 1.6 to 14 ng/mL. Study limitations include potential laboratory or collection errors and missing data. (i) Providers must be vigilant for signs of fentanyl patch abuse. (ii) Postmortem blood concentrations are not static postmortem, likely secondary to decreasing pH, increased aqueous solubility, and tissue redistribution, and are therefore unlikely to accurately represent antemortem blood concentrations.
... Fentanyl is a powerful synthetic opioid analgesic similar to morphine but 50-100 times more potent (2). It is classified under the United States (US) Controlled Substance Act as a Schedule II substance based on its accepted use in medical practice and high abuse potential. ...
... The presence of fentanyl analogs and other synthetic opioids in postmortem casework is alarming, as many have increased potency compared to fentanyl and exhibit similar pharmacological effects. Fentanyl causes dose-dependent central nervous system and respiratory depression through agonist activity at the μ-opioid receptor (2). Consequently, many fentanyl analogs exhibit enhanced effects at much lower dosages, thereby dramatically increasing the risk of fatal overdose. ...
Since 2013, the Miami-Dade County Medical Examiner Department has experienced an increase in the number of opioid-related deaths. The majority of cases coincided with the introduction of fentanyl into the local heroin supply. From 2014 to 2015, Miami-Dade County experienced a near 600% increase in fentanyl-related deaths, followed by an additional 200% increase in 2016. In 2015, two novel fentanyl analogs were identified in medical examiner cases: beta-hydroxythiofentanyl and acetyl fentanyl. In 2016, four additional fentanyl analogs emerged: para-fluoroisobutyryl fentanyl, butyryl fentanyl, furanyl fentanyl and carfentanil, as well as the synthetic opioid U-47700. In order to address this epidemic, a method was developed and validated to identify 44 opioid-related and analgesic compounds in postmortem samples using ultra high performance liquid chromatography ion trap mass spectrometry with MSn capabilities. The limit of detection for all compounds ranged from 0.1 to 5 ng/mL, with a majority having MS3 spectral fragmentation. Blood, urine, liver or brain specimens from ~500 postmortem cases were submitted for analysis based on case history and/or initial screening results. Of those cases, 375 were positive for illicit fentanyl and/or one or more fentanyl analogs. Due to the potency of these compounds, they were almost always included in the cause of death. Worth emphasizing and extremely alarming is the detection of carfentanil in 134 cases, 104 of which were initially missed by gas chromatography mass spectrometry. By incorporating this sensitive, highly specific, and evolving screening procedure into the workflow, the toxicology laboratory continues to effectively assist the medical examiners in determining the cause and manner of death of decedents in Miami-Dade County.
... The therapeutic plasma concentrations of fentanyl are varying according to the dose and the delivery formulation. Transdermal formulations lead to therapeutic concentrations between 0.3 and 1.5 ng/ml [5]. Intravenous administrations Electronic supplementary material The online version of this article ( ...
... The therapeutic plasma concentrations of fentanyl are varying according to the dose and the delivery formulation. Transdermal formulations lead to therapeutic concentrations between 0.3 and 1.5 ng/ml [5]. Intravenous administrations Electronic supplementary material The online version of this article (doi:10.1007/s00228-017-2272-9) contains supplementary material, which is available to authorized users. ...
... Using postmortem blood and urine norfentanyl/fentanyl ratios in the investigation of fentanyl-related deaths Sir, Deaths in which fentanyl is detected challenge medical examiners, who must decide whether a given death represents therapeutic administration or was an overdose. [1] Numerous independent studies have demonstrated there can be a significant overlap in concentration range between cases where fentanyl was deemed to have played a role in the death (overdose) and those where the finding of fentanyl was considered noncontributory (natural or incidental). [1] We believe this is especially true when fentanyl is involved along with other drugs, i.e., when one needs to find out, with some degree of certainty, whether acute fentanyl toxicity did occur and caused the death of the patient. ...
... [1] Numerous independent studies have demonstrated there can be a significant overlap in concentration range between cases where fentanyl was deemed to have played a role in the death (overdose) and those where the finding of fentanyl was considered noncontributory (natural or incidental). [1] We believe this is especially true when fentanyl is involved along with other drugs, i.e., when one needs to find out, with some degree of certainty, whether acute fentanyl toxicity did occur and caused the death of the patient. We propose that ratios of postmortem blood and urine norfentanyl/fentanyl may be helpful in predicting the role of fentanyl in patient's death. ...
... In the living, the dose administered generally correlates with measured blood concentrations. In the postmortem setting, however, there are several factors that may affect the concentration and should be considered when interpreting postmortem concentrations [7,[25][26][27][28][29]. These include tolerance, postmortem intervals and redistribution, and metabolism. ...
Introduction:
Transdermal fentanyl, an opioid used for management of marked pain, also is abused and may cause death.
Methods:
We reviewed medical examiner reports of 92 decedents who had one or more fentanyl transdermal patches on their body and had fentanyl detected in their postmortem toxicology analysis.
Results:
The manners of death included 40 accidents, 36 natural, 8 suicides, 5 therapeutic complications, and 3 undetermined deaths. Among the accidental fentanyl intoxication deaths, 32 of 37 involved substance abuse. The majority (95 %) of the 37 accidental deaths involving fentanyl were multi-drug intoxications. The substance abuse deaths had a mean fentanyl blood concentration (26.4 ng/ml or μg/L) that was over twice that of the natural group (11.8 ng/ml). Our analysis suggests a relationship between total patch dosage and mean postmortem fentanyl concentration up to the 100-μg/h dose.
Conclusions:
The very wide and overlapping ranges of postmortem fentanyl concentrations effectively nullify the utility of correlating the dose and expected postmortem concentration for any particular death. Based on the variable relationship between dose and blood concentration, the antemortem dose cannot be reliably predicted based on the postmortem concentration. This does not, however, render the medical examiner/coroner unable to determine the cause and manner of death because the toxicology results are only one datum point among several that are considered. Although there was a weakly positive relationship between body mass index and fentanyl concentration, further research is needed to determine whether adipose tissue represents a significant depot for postmortem release of fentanyl.
... Fentanyl is a highly effective opioid analgesic, indispensable for treatment of chronic pain, and a drug with high potential for abuse (11 -13). Indicated for use in the treatment of persistent pain of a moderate-to-severe degree, fentanyl provides therapeutic analgesia and exerts its principal pharmacologic effects on the central nervous system (13,14). The intrinsic danger of fentanyl lies in its potency; estimates place fentanyl at roughly 50-100 times the strength of morphine (11). ...
Drug concentration is a factor in the determination of the manner of death, but considerable overlap exists between therapeutic and toxic concentrations. This study aims to quantify opioid mortality in Kansas from use of fentanyl, methadone and oxycodone and to evaluate utility of drug concentrations for the determination of the manner of death. Cases referred to a forensic pathology practice in Kansas for autopsy from 1 January 2001 to 31 December 2011 were considered. The criterion for inclusion was detection of fentanyl, methadone and/or oxycodone in postmortem toxicology. Of 9,789 cases, 3,315 had positive toxicology: 180 of fentanyl, 299 of methadone and 310 of oxycodone. There were 207 single opioid fatalities, 264 polydrug overdoses and 318 deaths where an opioid was present but not contributory to the mechanism of death. In line with published studies, incidence of opioid overdose deaths increased over the time of the study. Drug concentrations within each cause and manner of death covered broad ranges. Non-natural and natural manners had less overlap than existed within non-natural manners in limited comparisons. This study shows that drug concentration is independent of manner for non-natural deaths and although insufficient to identify intent, can provide a guideline in differentiating non-natural from natural deaths.
... Au début des années 1990, l'introduction des dispositifs transdermiques (TD) au fentanyl (Durogesic 1 , Matrifen 1 ) a représenté une avancée importante pour le traitement des douleurs sévères et chroniques rebelles aux autres classes d'antalgiques. Ces traitements ne sont cependant pas dépourvus d'effets secondaires et possèdent un important potentiel de mésusage, comme en témoigne une littérature internationale relativement abondante [1,7,8] ; peu d'observations de surdosages semblent en revanche avoir été publiées en France. Nous présentons ici une série originale de 9 décès associés à l'utilisation de patches au fentanyl, adossée à une revue de la littérature insistant notamment sur les difficultés d'interprétation au plan médico-légal et toxicologique. ...
Une série de 9 décès intervenus dans un contexte d’usage ou de mésusage de dispositifs transdermiques (TD) à base de fentanyl (Durogesic® ou génériques) est rapportée. Les observations concernent 5 hommes et 4 femmes âgés de 26 à 73 ans, avec un nombre de patches impliqués compris entre 1 et 16 (doses de 48 à 1500 μg/h). Huit cas correspondaient à des applications multiples de patches au niveau cutané (avec dans un cas une possible injection intraveineuse associée du fentanyl recueilli par déconditionnement d’un ou plusieurs patches), et un cas à l’ingestion d’un patch. Les concentrations sanguines en fentanyl variaient de 2,2 à 234 ng/mL. Au vu des données de la littérature, les auteurs insistent sur les difficultés d’interprétation posées par ces situations médico-légales, s’agissant notamment d’apprécier la responsabilité du ou des dispositif(s) TD dans la survenue du décès ; plusieurs facteurs (proximité voire recouvrement entre taux sanguins thérapeutiques et toxiques, fréquence des polyintoxications, redistribution post-mortem) rendent compte de ces interprétations délicates, et imposent de considérer chaque situation au cas par cas, non seulement au vu des taux sanguins mais aussi de l’ensemble des données disponibles (anamnèse, autopsie, histologie).
... Variability in concentrations of a drug and its metabolites can be caused by differences in the administered dose, the victim's metabolism, the time interval between exposure to a drug and death, post-mortem processes (e.g. redistribution) and the time interval between death and sampling [22,25]. Moreover, toxic doses are known to be higher for chronic Table 5 Thirteen post-mortem forensic cases. ...
Narcotic analgesics are widely (ab) used and sometimes only occur in low concentrations in biological samples. Therefore, a highly sensitive liquid chromatography tandem mass spectrometry method was developed for simultaneous analysis of 9 narcotic analgesics and metabolites (buprenorphine, O-desmethyltramadol, fentanyl, norbuprenorphine, norfentanyl, pethidine, piritramide, tilidine and tramadol) in urine and whole blood. Sample preparation was performed on a mixed-mode cation exchange solid phase extraction cartridge with an additional alkaline wash step to decrease matrix effects and thus increase sensitivity. Ionization with electrospray ionization was found to be more efficient than atmospheric pressure chemical ionization. The use of a mobile phase of high pH resulted in higher electrospray ionization signals than the conventional low pH mobile phases. In the final method, gradient elution with 10mM ammonium bicarbonate (pH 9) and methanol was performed on a small particle column (Acquity C18, 1.7 μm, 2.1 mm × 50 mm). Selectivity, matrix effects, recovery, linearity, sensitivity, precision, accuracy and stability were validated in urine and whole blood. All parameters were successfully evaluated and the method showed very high sensitivity, which was the major aim of this study. The applicability of the method was demonstrated by analysis of several forensic cases involving narcotic analgesics.
... Past medical history and ante-mortem distribution, scene investigation, post-mortem examination, and toxicological results must all be carefully considered and interpreted case by case (Thompson et al., 2007;Nelson & Schwaner, 2009;Palmer, 2010, Krinsky et al., 2011. ...
... There has been suggestion that concentrations above this, particularly with concomitant drug use, may be considered potentially toxic (40). Palmer describes the significant overlapping of fentanyl concentrations when comparing the ranges for deceased following intravenous or transdermal patch use, with the later generally having higher concentrations (52). The mean measured fentanyl blood concentration in six transdermal fentanyl fatalities was 21 ng/mL (10-38 ng/mL) (9). ...
The prevalence of opioid use in therapeutic and recreational settings has steadily increased throughout the western world. The addition of fentanyl into heroin products can produce potentially dangerous consequences, even to opioid tolerant individuals who may be unaware of such additions. Following an observed spike of heroin-fentanyl related deaths in Melbourne, Australia, a study was undertaken to determine the prevalence of these cases. All reportable deaths occurring in Victoria during 2015 and submitted to the toxicology laboratory were analysed using LC-MS-MS to confirm the combination of the heroin marker 6-acetylmorphine and/or morphine, and fentanyl. Over 4,000 coronial cases in 2015 underwent toxicological analysis for these drugs, there were nine cases identified that involved fentanyl-laced heroin. There was no specific mention of fentanyl use in any of these cases. All occurred within 2 months and in two distinct locations. The first four deaths occurred within 3 days of each other, in neighboring suburbs. The ages ranged from 25 to 57 years with an average of 40 and median of 37 years, and consisted of eight males and one female. The average and median femoral blood concentration of fentanyl was 18 and 20 ng/mL (range: <1-45 ng/mL), and morphine 140 and 80 ng/mL (range: 20-400 ng/mL), respectively. All nine cases had 6-acetylmorphine detectable in blood. Urine analysis was also performed where available. A syringe, powder and spoon found at the scene of one case were also analysed and found to be positive for both heroin and fentanyl, which supported the likelihood of fentanyl-laced heroin. This is the first reported case series of fatalities involving heroin and fentanyl outside of North America in published literature. These findings may help inform public health and prevention strategies serving to decrease the potential for such fatalities in the future.
... Furthermore, the solubility of fentanyl is strongly influenced by pH with the consequence of higher fentanyl redistribution caused by decreased pH-values after death. Postmortem movement of fentanyl along a concentration gradient from tissue stores into the blood with subsequent increased solubility and ion-trapping in the acidic blood was assumed [21]. ...
Background:
Interpretation of postmortem fentanyl concentrations after transdermal application remains a challenge. There are indications that fentanyl shows relevant postmortem redistribution. The aim of this study was to investigate the time course of these changes and to develop recommendations for toxicological case work.
Material and method:
Blood specimens were collected from palliative care patients who were treated with fentanyl transdermal patches. Antemortem reference samples (ethylenediaminetetraacetic acid (EDTA) and serum specimens) were collected at stable dose rates. Postmortem femoral venous blood specimens were collected at four postmortem time-points: 2hpm (hours postmortem), 6-8hpm, 11-16hpm and approximately 24hpm. Liquid chromatography tandem mass spectrometry was applied to quantify fentanyl and norfentanyl.
Results:
Ten patients were included in the study (8 men, 2 women). Fentanyl patches with delivery rates of 12-150μg/h were applied. Antemortem fentanyl levels in EDTA samples varied between 0.19 and 4.64μg/L. At 6 to 8hpm, blood concentrations of fentanyl were already significantly (p=0.05) higher in postmortem samples compared to the paired antemortem reference. On average, the antemortem concentration (range: 0.19-4.64μg/L) increased 3-fold within 6-8hpm (range: 0.4-14.9μg/L), and 5.5-fold within 24hpm (range: 0.39-21.88μg/L). Norfentanyl concentrations increased significantly (p=0.01) within 6-8hpm, too. In half of the patients, norfentanyl concentrations were below fentanyl concentrations, antemortem as well as postmortem.
Conclusion:
Postmortem fentanyl concentrations increased quickly. As early as 6-8h after death, postmortem concentrations differ significantly from antemortem ones. Our results strongly indicate that postmortem blood concentrations of fentanyl after transdermal application should be interpreted carefully.
... Fentanyl concentrations are routinely investigated in postmortem samples (14,(61)(62)(63). To evaluate this application, postmortem blood was spiked at QC levels (7.50 and 75.0 ng/mL), spotted, dried, extracted and quantitated using whole blood DBS. ...
Fentanyl, and the numerous drugs derived from it, are contributing to the opioid overdose epidemic currently underway in the USA. To identify human exposure to these growing public health threats, an LC-MS-MS method for 5 μL dried blood spots (DBS) was developed. This method was developed to detect exposure to 3-methylfentanyl, alfentanil, α-methylfentanyl, carfentanil, fentanyl, lofentanil, sufentanil, norcarfentanil, norfentanyl, norlofentanil, norsufentanil, and using a separate LC-MS-MS injection, cyclopropylfentanyl, acrylfentanyl, 2-furanylfentanyl, isobutyrylfentanyl, ocfentanil and methoxyacetylfentanyl. Preparation of materials into groups of compounds was used to accommodate an ever increasing need to incorporate newly identified fentanyls. This protocol was validated within a linear range of 1.00-100 ng/mL, with precision ≤12% CV and accuracy ≥93%, as reported for the pooled blood QC samples, and limits of detection as low as 0.10 ng/mL. The use of DBS to assess fentanyl analog exposures can facilitate rapid sample collection, transport, and preparation for analysis that could enhance surveillance and response efforts in the ongoing opioid overdose epidemic.
... An important consideration of the findings of this study involves the current climate where synthetic opioids, including fentanyl, may be entirely used or sold in place of heroin. Fentanyl is highly potent, approximately 50-100 times more potent than morphine, has a fast onset of action and a narrow therapeutic window leading to the rapid onset toxic effects [48]. The adulteration of heroin with fentanyl has had a major impact on the number of opioid-related deaths in some areas and provided an additional challenge for healthcare providers in the safe and effective management of overdose cases [49,50]. ...
Background: The aim of this study was to investigate the safety of the management of non-fatal heroin overdose in the out-of-hospital environment; irrespective of whether or not naloxone had been administered. Heroin toxicity-related deaths as well as heroin intoxication-related traumatic deaths following patient-initiated refusal of transport were investigated.
Methods: Heroin-related deaths in the state of Victoria, Australia between 1 January 2012 and 31 December 2013 were investigated and data linkage to pre-hospital Emergency Medical Services performed, in order to identify whether the death was related to the last episode of care by paramedics. The number of non-fatal heroin overdose events over the study period were also examined.
Results and discussion: There were a total of 3921 heroin-related attendances by paramedics during the study period, including 2455 cases that involved treatment but where the patient was not transported to hospital. There were also 243 heroin-related deaths identified over the study period and 93% (n = 225) of those cases were matched with Ambulance Victoria electronic patient care records. Data linkage revealed 31 heroin-related deaths where there had been a recent presentation with a non-fatal heroin overdose to paramedics; however, none of these deaths were related to that episode of care, including for 11 individuals that were treated on scene by paramedics but not transported to the hospital.
Conclusions: This study demonstrated that the treatment of uncomplicated heroin overdose in the out-of-hospital environment was safe in terms of mortality, irrespective of whether or not naloxone had been administered. In all of the non-fatal heroin toxicity cases attended by paramedics, whether or not transported to hospital, death occurred as a result of a subsequent and unrelated heroin overdose.
Opioids cause a well-recognized toxidrome including respiratory depression, decreased conscious level, constricted pupils and hypotension. In overdose, their toxicity relates to both the amount ingested and the speed of absorption. People who regularly misuse opioids develop tolerance to the pharmacological effects over time and may seek higher doses to achieve the same desired effect. This also has important implications for users following periods of abstinence (e.g. while in custody), when tolerance can be lost, resulting in unanticipated toxic clinical effects when users return to their 'normal' dose. Similarly, variability in the potency of illegally obtained opioid drugs, which may or may not contain adulterants, leads to unpredictable pharmacological effects. Naloxone is the opioid antagonist of choice, and its dose should be titrated according to clinical response. The duration of action of naloxone is relatively short, and repeated doses or a continuous infusion may be required.
Fentanyl transdermal patches have been used to treat cancer‐ and noncancer‐related chronic pain. However, its inappropriate or illegal application may cause fatal poisoning. We herein present the case of a Japanese woman in her 40s who was found dead with seven 25‐μg/h fentanyl transdermal patches on her body. We established a detailed toxicological analysis procedure to quantify fentanyl, and its metabolite norfentanyl, and other drugs (acetaminophen, allylisopropylacetylurea, celecoxib, estazolam, promethazine, and sertraline) in human whole blood by ultra‐high‐performance liquid chromatography–tandem mass spectrometry. The measured fentanyl and norfentanyl concentrations in the femoral and cardiac blood were 0.051 and 0.072 μg/mL and 0.033 and 0.076 μg/mL, respectively. The decedent's fentanyl concentrations were consistent with previously reported postmortem blood levels for fatal cases of poisoning by fentanyl transdermal patches. Based on the decedent's case history, autopsy findings, and toxicological analyses, the cause of death was identified as intoxication with transdermal fentanyl.
Herein, we report a case of an assisted suicide committed by application of 34 matrix-based fentanyl-containing transdermal therapeutic systems (TTS) with different release rates. The TTS were supplied by the husband but administered by the deceased herself. Besides routine systematic toxicological analysis (STA), the concentrations of fentanyl and norfentanyl were determined in the blood (femoral and heart), urine, stomach content, brain, lung tissue, musculus iliopsoas, liver, kidney, bile and in some of the used TTS by LC-MS/MS. Blood levels of fentanyl were 60.6 μg/L in femoral blood and 94.1 μg/L in heart blood. These concentrations are in good concordance with levels described in cases with accidental or lethal suicidal fentanyl patch application. The organ distribution indicates an influence of post-mortem redistribution. The levels of residual fentanyl in the TTS were also determined. STA furthermore revealed supratherapeutic levels of bromazepam. Thus, the cause of death was a combination of fentanyl and bromazepam intoxication. However, considering the determined levels of fentanyl and norfentanyl in the entire set of specimens and the high toxicity in comparison to bromazepam, fentanyl was the leading toxic noxa.
The correct interpretation of postmortem toxicology results offers an explanation on the meaning and significance of the obtained analytical results. Interpretation agreement to reality will depend on the quality of the sample and analytical results. It will also depends on the knowledge of the existence of different postmortem phenomena and the circumstances in which the death occurred. The whole process is hampered by the lack of recommendations or protocols to guide the toxicologist in the process of interpretation. Therefore, it is the more complex stage of toxicological research. In order to assist the forensic toxicologist in this task, this review of the existing knowledge on this matter is presented.
Fentanyl is a synthetic opioid agonist used for pain control. Often administered as a transdermal patch, it is an interesting drug for study of postmortem redistribution. We hypothesized that fentanyl concentrations would increase over time after death, as measured in blood drawn on the day prior to autopsy and in blood drawn at the time of autopsy in ten cases where fentanyl patches were identified at the scene. Concentrations were compared, and heart blood to femoral blood ratios were calculated as markers of postmortem redistribution. Fentanyl concentrations measured in peripheral blood drawn the day of autopsy (peripheral blood 2 [PB2]) were higher than those drawn the day prior to autopsy (peripheral blood 1 [PB1]) with a mean ratio (PB2/PB1) of 1.80. The ratio of heart blood concentrations (HB) to femoral blood concentrations drawn at autopsy (PB2) had a mean ratio (HB/PB2) of 1.08. Some cases had blood from the same source analyzed at two different laboratories, and concentrations of fentanyl in those samples showed inter- and intralaboratory differences up to 25 ng/mL. Postmortem fentanyl concentrations may be affected by antemortem factors, postmortem redistribution, and laboratory variability. Forensic pathologists must use caution in interpreting fentanyl levels as part of death investigation.
In the course of the last decade, a substantial growth of new psychoactive substances (NPS) has been recorded. Within this group, a considerably fast growing sub-group is represented by the opioids, which are based on modifications of the fentanyl structure. In this study, identification and analytical characterization of a new fentanyl derivative, 4-fluorobutyrfentanyl (1-((4-fluorophenyl)(1-phenethylpiperidin-4-yl)amino)butan-1-one, 4-FBF), is described. Apart from the seized powder, 4-FBF was also identified in the e-cigarette liquid secured in Case 1. The concentration of the compound in the liquid was 35 mg/ml. The main component of the liquid was glycerol and nicotine was also present in the liquid. This substance was detected in seized material that originated from the illegal drug market in Poland. To the best of the authors’ knowledge, this report presents the first two analytically confirmed cases of fatal intoxication associated with 4-FBF. Case 1 was a 26-year old male drug user who was found dead at home. Case 2 was about a 25-year old female, occasional user of NPS and drugs, who was also found dead at home. The concentrations of 4-FBF in blood were 91 and 112 ng/mL and in urine 200 and 414 ng/mL. The concentrations of 4-FBF in liver and kidney were 902 and 411 ng/g, and 136 and 197 ng/g, for case 1 and case 2, respectively.
Fentanyl deaths have increased with availability of transdermal patches. Interpretation of postmortem fentanyl levels may be complicated by postmortem redistribution and absorption of fentanyl from a patch. We applied an unused 100-μg/h fentanyl patch onto the lower abdomen of a decedent with no premortem fentanyl exposure. Ocular fluid, blood, and urine were collected prior to placement, and the decedent was refrigerated for 23 h. Prior to the autopsy, urine, subcutaneous tissue under the patch, and samples from the same anatomic sites were obtained. We observed no fentanyl in any postpatch placement samples (LOD: 0.1 ng/mL for blood and vitreous fluid, 1.0 ng/mL urine, 2.0 ng/g for tissues). Although we observed no postmortem absorption of fentanyl, this was only a single case; therefore, we recommend that patches be removed after receipt of a cadaver before initiation of an autopsy, with the location of removed patch documented.
© 2015 American Academy of Forensic Sciences.
Two cases of poisoning involving two physicians (an anesthesiologist and a cardiologist) are herein presented. In both cases, autopsy and toxicological analyses were requested for forensic purposes. A systematic toxicological analysis by gas chromatography-mass spectrometry or liquid chromatography with tandem mass spectrometry was applied to biological specimens collected at autopsy and on paraphernalia (vials, residues within bottles, used syringes, and needles) seized at the scene of death. Each positive result obtained by systematic toxicological analysis was confirmed by a specific quantitative gas chromatography-mass spectrometry analysis. In the first case, fentanyl was revealed in the bottles and in all biological specimens in concentrations above the pharmacological levels. In the second case, biological samples were positive for phenobarbital, morphine, and codeine, but only phenobarbital was present at lethal concentrations. Morphine, codeine, papaverine, noscapine, and phenobarbital were identified on the syringe. The toxicological results in the present cases were compared with data reported in other cases of suicides involving fentanyl and phenobarbital. Risk factors linked to suicide in physicians and the general population were also discussed.
Opioids cause a well-recognized toxidrome including respiratory depression, decreased conscious level, pin point pupils and hypotension. In overdose their toxicity relates to both the amount ingested and speed of absorption. Addicts run into difficulty when a supply changes or adulterants are added, or they have had a period of relative abstinence resulting in loss of tolerance. Some opioids, such as dextropropoxyphene, methadone and tramadol, have additional properties that account for their toxicity. Naloxone is the opioid antagonist of choice and its dose should be titrated according to clinical response. Duration of action is relatively short and repeated doses or infusion may be required. Paradoxical increase in toxicity may be seen if some drug is unabsorbed in the gut before naloxone administration as gut motility recommences.
Synthetic opioids are responsible for numerous overdoses and fatalities worldwide. Currently, fentanyl and its analogs are also mixed with heroin, cocaine and methamphetamine, or sold as oxycodone, hydrocodone and alprazolam in counterfeit medications. Microextraction techniques became more frequent in analytical toxicology over the last decade. A method to simultaneously quantify nine synthetic opioids, fentanyl, sufentanil, alfentanil, acrylfentanyl, thiofentanyl, valerylfentanyl, furanylfentanyl, acetyl fentanyl and carfentanil, and two metabolites, norfentanyl and acetyl norfentanyl, in urine samples by microextraction with packed sorbent (MEPS) and liquid chromatography—tandem mass spectrometry (LC-MS/MS) was developed and validated. A multivariate optimization was performed to establish the number and speed (stroke) of draw-eject sample cycles and the extraction solvent. The best extraction condition was eight draw-eject sample cycles, with a velocity of 3.6 µL/sec and acetonitrile as elution solvent. Linearity was achieved between 1 to 100 ng/mL, with a limit of detection (LOD) of 0.1 ng/mL and limit of quantification (LOQ) of 1 ng/mL. Imprecision (% relative standard deviation) and bias (%) were less than 12.8% and 5.7%, respectively. The method had good specificity and selectivity when challenged with 10 different matrix sources and 36 pharmaceuticals and drugs of abuse at concentrations of 100 or 500 ng/mL. The method was successfully applied to authentic urine samples. MEPS was an efficient semi-automatic extraction technique, requiring small volumes of organic solvents (640 µL) and sample (200 µL). The cartridges can be cleaned and reused (average of 150 sample extractions/barrel inside and needle).
The United States Food and Drug Administration (FDA) has received numerous reports of serious adverse events, including death, in patients using fentanyl transdermal systems (FTS). To gain a better understanding of these problems, the current research focuses on the in vitro characterization of fentanyl reservoir (Duragesic) and matrix (Mylan) systems with respect to drug release and skin permeation under conditions of elevated temperature and compromised skin. In addition, different synthetic membrane barriers were evaluated to identify the one that best simulates fentanyl skin transport, and thus may be useful as a model for these systems in future studies. The results indicate that reservoir and matrix FTS are comparable when applied to intact skin at normal skin temperature but the kinetics of drug delivery are different in the two systems. At 40 degrees C, the permeation rate of fentanyl was twice that seen at 32 degrees C over the first 24 h in both systems; however, the total drug permeation in 72 h is significantly higher in the reservoir FTS. When applied to partially compromised skin, matrix FTS has a greater permeation enhancement effect than reservoir FTS. The intrinsic rate limiting membrane of the reservoir system served to limit drug permeation when the skin (barrier) permeability was compromised. Different ethylene vinyl acetate membranes were shown to have fentanyl permeability values encompassing the variability in human skin. Results using the in vitro model developed using synthetic membranes suggest that they mimic the effect of compromised skin on fentanyl permeability. Especially for highly potent drugs such as fentanyl, it is important that patients follow instructions regarding application of heat and use of the product on compromised skin.
Fentanyl is used in obstetrical practice to promote analgesia and anesthesia during labor and in cesarean delivery, with rapid and short-term effects.
To determine fentanyl concentrations in maternal plasma, in the placental intervillous space, and in the umbilical artery and vein in term pregnant women.
Ten healthy pregnant women underwent epidural anesthesia with fentanyl plus bupivacaine and lidocaine, and fentanyl concentrations were determined in the various maternal and fetal compartments, including the placental intervillous space, which has not been previously studied in the literature.
The ratios of fentanyl concentrations in the various maternal and fetal compartments revealed an 86% rate of placental fentanyl transfer. The highest fentanyl concentrations were detected in the placental intervillous space, being 2.19 times higher than in maternal plasma, 2.8 times higher than in the umbilical vein and 3.6 times higher than in the umbilical artery, with no significant differences between the umbilical vein and artery, demonstrating that there was no drug uptake by fetal tissues nor metabolism of the drug by the fetus despite the high rates of placental transfer.
The present study demonstrated that the placental intervillous space acted as a site of fentanyl deposit, a fact that may be explained by two hypotheses: (1) the blood collected from the placental intervillous space is arterial and, according to some investigators, the arterial plasma concentrations of the drugs administered to patients undergoing epidural anesthesia are higher than the venous concentrations, and (2) a possible role of P-glycoprotein (P-gp).
This study evaluated the validity of measuring fentanyl concentrations in equine plasma using radioimmunoassay (RIA) by comparing it to the established technique of liquid chromatography-mass spectrometry (LC-MS). Equine plasma samples were analyzed using a solid-phase Coat-A-Count fentanyl RIA and a validated LC-MS method. The fentanyl concentrations derived by both methods were compared by linear regression and pharmacokinetic analysis. The cross-reactivity of the primary equine fentanyl metabolite, N-[1-(2-phenethyl-4-piperidinyl)]maloanilinic acid (PMA), with the RIA was determined. The binding potency of fentanyl and PMA were compared at three opioid receptor subtypes in equine cerebral cortex using a radioligand binding technique. Fentanyl concentrations determined by RIA and LC-MS correlated, but the RIA overestimated low fentanyl concentrations and underestimated high fentanyl concentrations. The overestimation of low fentanyl concentrations is most likely due to the 29% cross-reactivity of PMA with the RIA. As a result, pharmacokinetic variables determined from an intravenous fentanyl bolus to four anesthetized horses differed depending on the analytical method. Although fentanyl bound with nanomolar potency to the three receptor subtypes, PMA exhibited no binding activity even at micromolar concentrations. In conclusion, when compared with LC-MS, fentanyl concentrations determined by RIA in equine plasma are misleading, especially for the calculation of fentanyl pharmacokinetics.
Postmortem changes in the pH of blood and selected tissues in rats were evaluated at intervals ranging from 2 min to 96 h. Cardiac blood pH was significantly and reproducibly decreased in all groups at all postmortem intervals, independent of the method of sacrifice used. A preliminary study using cardiac blood obtained at autopsy from a limited number (n = 11) of human subjects demonstrated a significant negative correlation (r = -0.908, P less than 0.01) between postmortem interval (range 2 to 20 h) and cardiac blood pH.
SUMMARY Plasma fentanyl concentrations were measured during and after transdermal fentanyl delivery in groups of patients undergoing
general surgery. At 8 and 12 h, concentrations did not differ from those observed in a matched group of patients receiving
fentanyl by i.v. infusion. At 24 h, concentrations were significantly lower in one of the transdermal groups. Plasma fentanyl
clearance did not differ significantly between the groups. Plasma fentanyl concentrations decreased slowly after removal of
the transdermal system.
Abstract Fentanyl is a synthetic opioid agonist which interacts primarily with the μ-opioid receptor. The low molecular weight, high potency and lipid solubility of fentanyl make it suitable for delivery by the transdermal therapeutic system. These patches are designed to deliver fentanyl at a constant rate (25, 50, 75 and 100 μg/h), and require replacement every 3 days. Data from randomised, nonblind trials suggest that transdermal fentanyl is as effective as sustained-release oral morphine in the treatment of chronic cancer pain, as reported by patients using visual and numerical analogue scales as well as verbal description scales. No obvious differences in health-related quality of life were found in patients with chronic cancer pain when comparing transdermal fentanyl with sustained-release oral morphine. Nevertheless, significantly more patients expressed a preference for transdermal fentanyl than for sustained-release oral morphine after a randomised, nonblind, crossover trial. Because of the formation of a fentanyl depot in the skin tissue, serum fentanyl concentrations increase gradually following initial application, generally levelling off between 12 and 24 hours. Thereafter, they remain relatively constant, with some fluctuation, for the remainder of the 72-hour application period. Once achieved, steady-state plasma fentanyl concentrations can be maintained for as long as the patches are renewed. The most frequently observed adverse events during transdermal fentanyl administration (as with other opioid agonists) included vomiting, nausea and constipation. Data from a nonblind, randomised trials suggest that constipation occurs less frequently in patients receiving transdermal fentanyl than in those given sustained-release oral morphine. The most serious adverse event reported in US premarketing trials was hypoventilation, which occurred with an incidence of approximately 2%. Adverse reactions related to skin and appendages (i.e. rash and application site reactions —erythema, papules, itching and oedema) were reported in 153 patients with cancer at a frequency between 1 and 3%. Conclusion: Transdermal fentanyl is a useful opioid-agonist for the treatment of moderate to severe chronic cancer pain. The advantages of transdermal fentanyl include ease of administration and the 3-day application interval. These factors coupled with a lower incidence of constipation are likely to contribute to the reported patient preference of transdermal fentanyl over sustained-release oral morphine. Pharmacodynamic Profile of Transdermal Fentanyl Fentanyl interacts with the μ-opioid receptor as a pure agonist. The analgesic potency of fentanyl is 75 to 100 times higher than that of morphine, probably because fentanyl is lipophilic, allowing rapid penetration of the blood-brain barrier. The mechanisms of opioid-induced analgesia are only partly understood. Like other opioid agonists, fentanyl can induce potentially life-threatening respiratory depression. Experiments in cats suggest that fentanyl-induced sustained inspiration (thoracic rigidity) results from increased amplified efferent activity to the spinal cord inspiratory motor neurons. Moreover, studies in rats suggest that fentanyl, unlike morphine, induces respiratory depression via the μ1-receptor. Constipation is a common adverse event after opioid administration. Subcutaneous administration of fentanyl and morphine to rats resulted in an analgesic peak effect at doses of 0.032 mg/kg and 8.0 mg/kg, respectively. This analgesic dose was only 1.1 times higher than the dose required for a 50% inhibition of castor oil-induced diarrhoea for fentanyl, but 36 times higher than that for morphine. These results suggest that fentanyl induces analgesia without incurring the same degree of constipation as morphine. Indeed, transdermal fentanyl administration appears to result in constipation in fewer patients when compared with oral morphine therapy as shown by clinical trials. Peripheral vasodilation and hypotension have been observed after intravenous morphine administration in surgical patients. In this study, however, such haemodynamic effects were not seen following fentanyl administration. There are two possible explanations for this difference. Firstly, morphine-induced vasodilation has been associated with histamine release. Unlike morphine, however, fentanyl administration did not lead to increased plasma levels of histamine. A second explanation could be that morphine, but not fentanyl, stimulates the release of the potent vasodilator nitric oxide by human endothelial cells in vitro by stimulation of the μ3-receptor. Pharmacokinetic Properties Fentanyl can be administered transdermally because of its high solubility in both fat and water and its low molecular weight. The application systems are designed to deliver fentanyl at a constant rate for periods of 72 hours. Currently, patches with a delivery rate of 25, 50, 75 and 100 μg/h are available. Neither local blood flow nor anatomical site of application seem to affect fentanyl delivery. Nonetheless, a rise in body temperature to 40°C may increase the absorption rate by about one-third. In general, the pharmacokinetics of transdermal fentanyl show interindividual variability. After intravenous administration, fentanyl has a high extravascular volume of distribution (3 to 8 L/kg) in surgical patients. In animals, the drug shows wide physiological distribution to the lungs, kidneys, heart, spleen, brain, muscles and body fat. After transdermal application, an average bioavailability of 92% has been estimated in surgical patients. Mean maximum plasma concentration (Cmax) values were 0.6, 1.4, 1.7 and 2.5 μg/L at delivery rates of 25, 50, 75 and 100 μg/h, respectively. Plasma concentrations were proportional to delivery rate. Delays of 34 to 38 hours have been reported between patch application (25 to 100 μg/h) and occurrence of Cmax. This delay is likely to be due to the formation of a fentanyl depot within the skin before the drug diffuses into the circulation. After several sequential 3-day (72-hour) application intervals, steady-state plasma fentanyl concentrations are achieved, which can be maintained for as long as the fentanyl patches are renewed. Fentanyl is mainly metabolised by cytochrome P450 (CYP) 3A4. The major metabolite is norfentanyl and minor metabolites include despropionylfentanyl, hydroxyfentanyl and hydroxynorfentanyl, none of which show clinically relevant pharmacological activity. Elimination of fentanyl after patch removal is slow; elimination half-life values of 13 to 22 hours have been reported. The slow elimination is likely to be due to the slow release of the drug from the skin depot. The total body clearance for fentanyl is 34.2 to 52.8 L/h. Since metabolisation of fentanyl is dependent on CYP3A4, coadministration of drugs that inhibit this isoenzyme may impair fentanyl clearance. Moreover, known CYP inducers may enhance fentanyl clearance. Therapeutic Use Randomised comparative trials in 40 to 127 patients with chronic pain associated with cancer have indicated that transdermal fentanyl 25 to 300 μg/h provides adequate pain control in 66 to 77% of patients. The only double-blind comparative trial of transdermal fentanyl, however, failed to show any statistically significant benefit over placebo. However, this study has not resulted in any significant doubt regarding the analgesic efficacy of transdermal fentanyl; indeed, treatment with transdermal fentanyl is well established and accepted in this indication, as indicated by recent review articles and treatment guidelines. There are a number of possible confounding factors that need to be considered when evaluating this study [including the absence of an active comparator and the possible masking of effects by rescue medication (oral morphine, 51 and 48 mg/day, respectively)]. Data from the two nonblind, randomised trials suggest that transdermal fentanyl is as effective as sustained-release oral morphine in the treatment of chronic cancer pain. No significant differences between transdermal fentanyl and sustained-release oral morphine were found for any of the efficacy parameters in the 2-week trials. In all trials, patients received oral morphine as rescue medication for breakthrough pain. In the randomised studies, patients were stabilised with morphine before being switched to fentanyl patches. The initial dose of transdermal fentanyl was based on the previous morphine dose as calculated by the conversion table supplied by the manufacturer. In general, the transdermal fentanyl patches were replaced every 72 hours. Pain control was assessed by the use of visual or numerical analogue scales and verbal descriptions by which patients could express pain intensity. Moreover, in three studies, quality-of-life parameters were assessed by elements from validated survey scales. Patients enrolled were adults experiencing chronic cancer pain and requiring strong opioid analgesia. Although possible advantages of transdermal fentanyl on health-related quality of life are difficult to appraise methodologically, they embody important elements of palliative care and are an important clinical outcome. A randomised nonblind trial revealed no significant differences in effect on social, physical, role, cognitive or emotional functioning or global quality of life between transdermal fentanyl and sustained-release oral morphine. Nonetheless, significantly more patients preferred transdermal fentanyl than sustained-release oral morphine and there were significant differences in favour of fentanyl in other quality-of-life parameters (e.g. interruption of daily activities of both patients and caregivers, convenience and satisfaction). Adverse Effects The most serious adverse event associated with transdermal fentanyl administration was hypoventilation, which occurred in approximately 2% of patients with cancer pain during a premarketing trial. As with other opioid agents, the most frequently observed adverse events during fentanyl treatment are nausea, vomiting and constipation. Nonblind clinical data, however, suggest that fentanyl is associated with less constipation than sustained-release oral morphine as assessed by patient questionnaires. Clinical data in patients with cancer reveal no obvious differences in the occurrence of nausea and vomiting when comparing transdermal fentanyl with sustained-release oral morphine. Adverse reactions related to skin and appendages (i.e. rash and application site reactions —erythema, papules, itching and oedema) were reported in 153 patients with cancer at a frequency between 1 and 2%. Opioid withdrawal symptoms may occur after discontinuation of transdermal fentanyl administration and after conversion from other opioid analgesics to transdermal fentanyl. Dosage and Administration Transdermal fentanyl is contraindicated in patients with acute postoperative pain and should not be administered to children under 12 years of age or to patients under 18 years of age who weigh less than 50kg (1101b). Moreover, the initial dosage should not exceed 25 μg/h in opioid-naive patients and elderly or severely debilitated patients taking less than 135 mg/day oral morphine or equivalent. Doses should be personalised according to the manufacturer’s recommended conversion ratio. According to the manufacturer’s recommendations, adjustment of the dosage should be withheld until 3 days after initial application and should then occur at 6-day intervals if necessary. It is important to stress that rescue medication such as immediate-release oral morphine should be readily available to the patient, especially during the titration period. The transdermal fentanyl patches should be applied to an intact, hair-free (clipped not shaved) area of the skin.
The transdermal fentanyl system delivers a specific dose at a constant rate. Even after the prescribed application time has elapsed, enough fentanyl remains within a patch to provide a potentially lethal dose. Death due to the intravenous injection of fentanyl extracted from transdermal patches has not been previously reported. We present 4 cases in which the source of fentanyl was transdermal patches and was injected. In all of these cases, the victim was a white male who died at home. Case 1 was a 35-year-old with no known history of drug use, who was found by his wife on the floor of his workshop. Police recovered a fentanyl patch, needle, and syringe at the scene. Case 2 was a 38-year-old with a known history of drug use whose family claimed that he was in a treatment program that used fentanyl patches for unknown reasons. His brother found him dead in bed, and law enforcement officers found a hypodermic needle beside the body; a ligature around his left hand, and apparent needle marks between his first and second digits were also noted. Case 3 was a 42-year-old with a recent attempted suicide via overdose who was found dead at his home. An empty box of fentanyl patches, Valium, Ritalin, and 2 syringes were found at the scene. Case 4 was a 39-year-old found by his mother, who admitted to removing a needle with attached syringe from the decedent's arm. Medications at the scene included hydrocodone, alprazolam, zolpidem, and fentanyl patches. All reported deaths were attributed to fentanyl intoxication, with blood concentrations ranging from 5 to 27 μg/L.
For many years it has become increasingly apparent from literature reports that the postmortem cardiac blood concentrations of certain drugs can be significantly different than those found in peripheral blood. The cardiac to peripheral ratio (C/P) of drug concentrations in postmortem blood samples was determined for 113 drugs representing toxicological findings in 320 cases. Theories postulated in current scientific literature to explain observed site dependence of drug concentration in postmortem blood are discussed in light of the findings. It is suggested that drug quantifications be done on both cardiac and peripheral blood and that the final interpretation of results be done as a team effort by all individuals involved in the death Investigation.
Regional differences in the permeability of human skin are well known but few investigators attempt to quantify the variability at specific sites as distinct from site-to-site differences. We assessed the variability at a site, within and between specimens (individuals). We defined the ultra-specimen variation (intra-s.v.) at a site as the coefficient of variation for a parameter measured for samples within a specimen; inter-specimen variation (inter-s.v.) was the coefficient for several specimens. We measured the steady-state diffusion of phenol, methanol, octanol and caffeine, and the finite dose diffusion of aspirin and caffeine and performed a vasoconstrictor assay with betamethasone-17-benzoate in 9 vehicles. From these data and from published results, we estimated inter-s.v. and intra-s.v. The overall mean, in vitro estimates of inter-s.v. (66% ± S.D. 25, n = 45) and intra-s.v. (43% ± 25, n = 32) were higher than the mean, in vivo, estimates of inter-s.v. (45% ± 18, n = 114) and intra-s.v. (27% ± 9, n = 4). Inter-s.v. was higher than intra-s.v. both in vivo and in vitro.
A 54-year old male (90 kg) was found in his bedroom with a fentanyl transdermal patch on his penis. Wi th low vital reactions, the dormant man was immediately br ought to hospital, where he died shortly. Systemati c toxico- logical analysis confirmed a fatal poisoning with f entanyl. The fentanyl concentration in blood was 35 .1 µg/L (LC-MS-MS). The presented case demonstrated the possibility of fentanyl misuse with a transdermal patc h at a place of possibel high resorption and fatal outcome . Death due to the application of fentanyl transder mal system which was patched on the penis has not been previou sly reported.
Clinical pharmacology assumes that deductions can be made about the concentrations of drugs from a knowledge of the pharmacokinetic parameters in an individual; and that the effects are related to the measured concentration. Post-mortem changes render the assumptions of clinical pharmacology largely invalid, and make the interpretation of concentrations measured in post-mortem samples difficult or impossible. Qualitative tests can show the presence of substances that were not present in life, and can fail to detect substances that led to death. Quantitative analysis is subject to error in itself, and because post-mortem concentrations vary in largely unpredictable ways with the site and time of sampling, as a result of the phenomenon of post-mortem redistribution. Consequently, compilations of 'lethal concentrations' are misleading. There is a lack of adequate studies of the true relationship between fatal events and the concentrations that can be measured subsequently, but without such studies, clinical pharmacologists and others should be wary of interpreting post-mortem measurements.
Fentanyl concentrations were measured in postmortem specimens collected in 20 medical examiner cases from femoral blood (FB), heart blood (HB), heart tissue, liver tissue, and skeletal muscle. Unique was a subset of 7 cases in which FB was obtained at 2 postmortem intervals, shortly after death (FB1) and at autopsy (FB2). The mean collection times of FB1 and FB2 after death were 4.0 and 21.6 hours, respectively. Fentanyl concentrations for FB1 and FB2 ranged from undetectable to 14.6 microg/L (mean, 4.6 microg/L) and 2.0 to 52.5 microg/L (mean, 17.3 microg/L), respectively. Corresponding mean HB, liver tissue, and heart tissue fentanyl concentrations were 29.8 microg/L, 109.7 mg/kg, and 103.4 mg/kg, respectively. The fentanyl HB/FB1 ratio (mean, 8.39) was higher compared with the corresponding HB/FB2 ratio (mean, 3.48). These results suggest that postmortem redistribution of fentanyl can occur in FB.
Fentanyl is a potent Schedule II narcotic analgesic recommended for use in the management of unremitting pain not controlled by morphine or other opiate/opioid drugs. The danger inherent to fentanyl is its potency (greater than 50-100 times that of morphine) and rapidity of action, causing respiratory depression within minutes of administration. Advisories have been issued on a state and national level to health care providers and through manufacturers' package inserts for patients. Still, as will be demonstrated in this case review, the use of only a single transdermal patch taken as prescribed for the first time can prove fatal. A drug that requires such extensive warnings-that if unheeded lead to death because of its narrow therapeutic/toxic window, should have strict criteria and limited outpatient use. Initial medical observation and documentation for determining tolerance might be required before issuing a prescription. There has been a rise in the popularity of this drug evidenced by increased deaths among drug abusers and more prescriptions written. In the year 2006, the Center for Forensic Sciences in Onondaga County had 8 cases where fentanyl was considered the cause of death, often with other drugs detected in therapeutic concentrations. This number was a marked increase from the 1 to 2 cases occurring annually from 2002 to 2005. All of these 2006 overdoses because of fentanyl involved the transdermal formulation. The investigative data, blood and liver fentanyl levels, and autopsy findings will be presented.
Objective:
To evaluate the underlying pharmacology, safety, and misuse/abuse of transdermal fentanyl, one of the cornerstone pharmacotherapies for patients with chronic pain.
Methods:
Literature was identified through searches of Medline (PubMed) and several textbooks in the areas of pharmacology, toxicology, and pain management. A bibliographical review of articles identified by these searches was also performed. Search terms included combinations of the following: fentanyl, transdermal, patch, pharmacology, kinetics, toxicity, and poisoning. All pertinent clinical trials, retrospective studies, and case reports relevant to fentanyl pharmacology and transdermal fentanyl administered by any route and published in English were identified. Each was reviewed for data regarding the clinical pharmacology, abuse, misuse, and safety of transdermal fentanyl. Data from these studies and information from review articles and pharmaceutical prescribing information were included in this review.
Results:
Fentanyl is a high-potency opioid that has many uses in the treatment of both acute and chronic pain. Intentional or unintentional misuse, as well as abuse, may lead to significant clinical consequences, including death. Both the US Food and Drug Administration (FDA) and Health Canada have warned of potential pitfalls associated with transdermal fentanyl, although these have not been completely effective in preventing life-threatening adverse events and fatalities related to its inappropriate use.
Conclusions:
Clinically consequential adverse effects may occur unexpectedly with normal use of transdermal fentanyl, or if misused or abused. Misuse and therapeutic error may be largely preventable through better education at all levels for both the prescriber and patient. The prevention of intentional misuse or abuse may require regulatory intervention.
Recently, there has been an increase in fentanyl-related overdoses following administration of transdermal patches by the buccal, oral or intravenous route or via inhalation. A fatal intoxication is reported with clear evidence from toxicological analysis. However, the administration route and the fate of the patch remained elusive at the end of the investigations. Alcohol was present in the blood in small quantity (0.024%), whereas no other drug could be detected by basic strategies. Autopsy and microscopic examination failed to find sufficient evidence for a diagnosis. Fentanyl and norfentanyl were determined from body fluids and tissues by LC/MS/MS following liquid/liquid extraction. Both analytes were detectable in all specimens under investigation except muscle tissue where norfentanyl was absent. While the fentanyl concentration in the blood was considered potentially life-threatening on the basis of data obtained from living persons and fentanyl-related deaths, it was difficult to assess the other values because no comparative data were available. The history and circumstances of the case together with the toxicological findings suggest an intravenous or inhalative application of the patch. The latter assumption is supported by the fact that the body was found holding a cigarillo butt in his right hand. The case underlines the necessity to study fentanyl-related deaths more closely to allow a better interpretation of potential intoxications.
Introduced into clinical practice in the 1960s, the analgesic fentanyl is 100 times more potent than morphine. Various methods of administration exist including the transdermal Duragesic patch system, widely used in chronic pain and palliative care settings. Numerous, often imaginative methods of abuse of fentanyl patches have been reported; the majority of fatal fentanyl overdose cases resulting from deliberate abuse or suicide. We describe the accidental overdose of a young black male with sickle cell/beta-thalassemia who had been using the Duragesic system for almost 2 years.At autopsy the macroscopic findings were of nonspecific opiate overdose with congested heavy lungs. Histopathological examination revealed severe sickling of red blood cells in the lungs (acute chest syndrome). Toxicological examination revealed blood and urine fentanyl levels of 40 microg/L and 400 microg/L (10 fold and 100 fold higher than therapeutic levels). The mast cell tryptase was also significantly elevated at 76 microg/L, (Normal 2-14 microg/L). We discuss the relevance of these findings with regard to the cause of death, and stress the need to consider fentanyl when confronted with nonspecific signs of opiate overdose as it is not detected in routine toxicological drug screens.
A 41-year-old white woman on long-acting opioid therapy was diagnosed with moderate obstructive sleep apnea. On initiation of continuous positive airway pressure (CPAP), she manifested severe central apnea that was unresponsive to supplemental oxygen and interfered with CPAP titration. Acetazolamide, 250 mg, nightly at bedtime was initiated, and CPAP titration was repeated. On acetazolamide, optimal CPAP pressure was obtained with no manifestation of clinically significant central respiratory disturbance. This case suggests that acetazolamide may be an effective adjunct to positive airway pressure therapy in patients on long-acting opioids. A need exists for examination of acetazolamide in this capacity.
The detection of acute fentanyl exposure in fresh and decomposed skeletal tissues (marrow and bone), by automated enzyme-linked immunosorbent assay (ELISA) is described. Rats (n=15) were administered fentanyl acutely at a dose of 0 (n=3), 15 (n=3), 30 (n=3) or 60 microg/kg (n=6) by intraperitoneal injection, and euthanized within 20 min. Femora and tibiae were extracted from the fresh corpses and marrow was isolated from the femoral and tibial medullary cavities. The remains were then allowed to decompose outdoors to the point of complete skeletonization, and vertebrae and pelvi were recovered for analysis. In all cases, bones were cleaned in alkaline solution and then ground into a fine powder. Marrow was homogenized in alkaline solution. Fentanyl was extracted from ground bone by methanolic extraction. Extracts were adjusted to pH 6 and analyzed by ELISA. Perimortem heart blood was also collected and diluted in phosphate buffer prior to screening by ELISA. The effect of tissue type on ELISA response was examined through determination of binary classification test sensitivity and the relative decrease in absorbance (%DA, drug-positive tissues vs drug-free controls) in each tissue type. Overall, the %DA varied significantly between extracts from different skeletal tissues under a given dose condition, according to the general order of marrow>vertebrae approximately pelvi>epiphyseal bone approximately diaphyseal bone. Binary classification test sensitivity values for fentanyl in marrow, fresh epiphyseal (femoral and tibial) bone, fresh diaphyseal (femoral and tibial) bone, decomposed vertebrae and decomposed pelvic bone were 100%, 16-33%, 0-16%, 0-33% and 66-100%, respectively, at the 60 microg/kg dose level. While mean %DA values showed a strong positive correlation with those in marrow and blood measurements and the administered dose (r=0.997 and 0.986), such a correlation was not observed in assays of decomposed tissues (r=-0.157 and -0.315). These results suggest that the type of skeletal tissue sampled and position within a given bone may be important considerations in the choice of substrate for fentanyl screening in skeletal tissues, but that quantitative analysis of drugs in decomposed bones may be of limited interpretive value.
Postmortem redistribution refers to the process of drugs diffusing from tissues into blood along a concentration gradient between death and time of specimen collection at autopsy. Anatomical site-to-site variation can exist for drug concentrations. The purpose of this study was twofold. First femoral blood, liver, and heart fentanyl concentrations were compared in medical examiner cases to assist in determining which specimen most appropriately should be used for interpretation. Nine fentanyl-positive cases were identified by history of drug use over a 15-month period (2007-2008). Femoral blood fentanyl concentrations (n = 9) ranged from 2.7 to 52.5 microg/L, liver fentanyl tissue (n = 9) ranged from 37.0 to 179 microg/kg, and heart fentanyl tissue (n = 3) ranged from 52.8 to 179 microg/kg. Liver tissue to femoral blood ratios ranged from 0.85 to 35.8, and heart tissue to femoral blood ratios ranged from 1.9 to 5.4. Second, utilizing a published compendium of multiple postmortem drugs, liver and heart tissues to femoral blood drug ratios were compared to known volumes of distribution, solubilities, and pKa. No significant relationships were observed. In conclusion, establishing a larger evidence-based database using liver fentanyl concentrations may be more optimal than blood concentrations for interpretation of postmortem fentanyl concentrations in medical examiner and coroner cases.
Postmortem drug concentrations may vary depending on sampling site, volume of blood collected, and method of sampling, making it important to analyze specimens from different sites in the body to detect postmortem redistribution and avoid erroneous conclusions on cause and manner of death. Using a blind stick method to draw large amounts of blood from the femoral vessel may increase the likelihood of contamination with blood from more central sites. It has been suggested that clamping the femoral vessel before drawing the sample may eliminate possible contribution from central sites. Eight drugs from four different drug classes were evaluated to determine the difference between drug concentrations in clamped and blind stick femoral blood. Drug concentrations of three selective serotonin reuptake inhibitors, or SSRIs (sertraline, paroxetine, citalopram), two benzodiazepines (diazepam and alprazolam), two antihistamines (diphenhydramine and promethazine), and one opiate (hydrocodone) were evaluated in clamped femoral blood, blind stick femoral blood, and heart blood and compared using concentration ratios and linear regression analysis. Clamped femoral blood concentrations and blind stick femoral blood concentrations were found to have good predictability across all drug classes with ratios around 1.0, indicating good correlation between blind stick femoral and clamped femoral samples. Therefore, it can be concluded that a blind stick femoral blood sample does not have significant redistribution from central sites and is of equivalent quality to a clamped femoral sample.
Due to the increasing prescription there are more and more cases of abuse and accidents related to fentanyl patches. The use of fentanyl patches (e.g. Durogesic) for committing suicide is rare, however. In our case, we describe a suicide with an amount of fentanyl patches never mentioned in the literature before. A depressive 63-year-old man was found dead in his apartment. On the body of the decedent 20 nearly symmetrically arranged fentanyl patches (Durogesic) of different strength with a total dose of 1350 microg/h were found. According to the results of the police the fentanyl patches were part of the pain therapy of his late wife, who had died one year before. Neither the autopsy nor the histological examinations revealed a cause of death. The chemical-toxicological investigation showed the following fentanyl concentrations: 94.9 ng/g (femoral vein blood), 45.9 ng/g (blood of the left heart), 74.8 ng/g (blood of the right heart), 101 ng/mL (urine), 468 ng/mL (bile), 745 ng/mL (stomach contents), 78.4 ng/mL (cerebrospinal fluid), 133 ng/mL (vitreous humor). The blood concentrations were in the upper range of the concentrations found in similar cases published. Hints for a postmortem increase of the fentanyl concentration because of the long postmortem interval of nearly 8 days were found.
The pharmacokinetics of fentanyl are complicated by an additional increase in plasma concentration during the elimination
phase of the drug. We have confirmed that fentanyl is excreted in the gastric juice and reabsorbed from the alkaline medium
of the small intestine. In addition, the stomach wall in rats has an important storage capacity for fentanyl. A maximum of
about 20% of the dose was found in the stomach wall after i.v. injection. In man the resected part of the stomach contained
16% of the dose, 10 min after injection. These observations could be important in explaining the occurrence of respiratory
depression in the period after operation.
In some cases of drug overdose there is a reservoir of unabsorbed drug in the stomach and gut. Furthermore, agonal aspiration might establish a second reservoir in the lungs. Two experimental rat models were used to study if diffusion from these reservoirs could contribute to the phenomenon of postmortem drug redistribution. Overnight fasted rats were sacrificed by CO2 and 75 mg of amitriptyline (AMI) was administered by a gastric tube. In the first series (n = 19), the tubes were removed after AMI administration. In the second series (n = 17), the trachea was ligated and cut prior to drug administration to prevent airways contamination. The rats were left at room temperature on their back for a period of 5, 10, 24, 48, 96 up to 192 h and samples of heart blood, blood from the inferior vena cava, tissue samples from heart, lungs, different liver lobes, kidney and psoas muscle were taken. In both series of rats we observed that as early as 5 h postmortem increasing concentrations of amitriptyline were found in the liver lobes lying closest to the stomach. In rats where the trachea was not ligated, drug contamination of the lungs also resulted in an increase in drug concentration within 5 h in heart blood and heart muscle. In rats where the trachea had been ligated, amitriptyline was found in the lungs after 96 h postmortem. The main metabolite nortriptyline was also detected.(ABSTRACT TRUNCATED AT 250 WORDS)
To review the mechanisms and sequence of events that occur during ischemia and cell death and following death of the human body. The impact of these postmortem events on the distribution and pharmacokinetic behavior of drugs is described. The case study presented illustrates a possible situation where such postmortem changes could have affected the pharmacokinetics of procainamide.
English-language journal articles and reference texts identified from pertinent data sources.
Postmortem changes in the human body begin at the cellular level with the onset of ischemia. As the length of time of ischemia increases and death ensues, more changes occur and lead to deterioration in tissue and organ function. These changes may affect the pharmacokinetic and distribution behavior of certain drugs. Drugs particularly affected are those whose distribution is dependent on molecular size, lipophilicity, pH, energy-dependent transport, and tissue binding. Such drugs include the tricyclic antidepressants, digoxin, and cimetidine. Other drugs with similar characteristics, such as procainamide, may also demonstrate like changes in distribution and pharmacokinetics.
When measuring drug concentrations after death, it is important to consider the phenomenon of postmortem redistribution. Postmortem drug concentrations may not be a true reflection of antemortem concentrations and as a result, wrong conclusions could be made about the cause of death. More studies characterizing the postmortem distribution and pharmacokinetic characteristics of specific drugs are necessary.
The physicochemical properties, pharmacology, pharmacokinetics, serum concentrations and clinical effects, adverse effects and contraindications, and dosage of transdermally administered fentanyl are described, and clinical studies evaluating the use of a transdermal fentanyl system in the treatment of postoperative pain and chronic cancer-associated pain are reviewed. After application of a transdermal system, fentanyl is absorbed into the skin beneath the patch, where a depot forms in the upper skin layers. Plasma fentanyl concentrations are barely detectable for about two hours after patch placement. Eight to 12 hours after patch placement, concentrations approximate those achieved with equivalent i.v. doses of fentanyl. Some studies comparing transdermally administered fentanyl with placebo in postoperative patients showed that the patients who received fentanyl required fewer supplementary analgesics and reported less pain than the patients who received placebo. However, the overall efficacy and safety of the transdermal fentanyl system for the treatment of postoperative pain have not been adequately evaluated. Studies of cancer patients showed that transdermally administered fentanyl appears to be effective in the management of chronic, cancer-related pain. Dermatological reactions to the fentanyl patch are generally transient and mild. Other adverse effects are those that are commonly associated with narcotic analgesics. The 25-micrograms/hr patch should be used for initial treatment in patients not previously treated with narcotics. The dosage may be gradually increased until effective analgesia is obtained. Although experience with the product is limited, transdermally administered fentanyl appears to be effective for the long-term management of cancer-related pain.
A fatality resulting from the self-administration of fentanyl is described. The deceased was a health care professional with
a known history of drug abuse. At the scene, a syringe partly filled with red fluid was found. Pathological findings disclosed
pulmonary congestion, hemorrhage, and aspiration of gastric contents and passive congestion in the liver and kidneys. Initial
drug screening revealed the presence of fentanyl in the fluid from the syringe and diazepam/oxazepam in the urine. Fentanyl,
diazepam, nordiazepam, and oxazepam in the submitted samples were simultaneously quantitated using a gas chromatograph equipped
with a nitrogen-phosphorus detector. The fentanyl concentrations (µg/L or µg/kg) in serum, blood, urine, bile, liver, kidney, brain, lung, and stomach tissue were 17.7, 27.5, 92.7, 58.2, 77.5, 41.5,
30.2, 83.4, and 31.6, respectively. The tissue levels of diazepam and its metabolites were lower than the reported lethal
concentrations. The fentanyl concentration in the syringe contents was 2,800 µg/L. The toxicological findings and circumstantial evidence of the case indicate that the death resulted primarily from fentanyl
overdose.
More than 80 deaths have occurred after the use of midazolam (Versed), often in combination with opioids, to sedate patients undergoing various medical and surgical procedures. We investigated the respiratory effects of midazolam (0.05 mg.kg-1) and fentanyl (2.0 micrograms.kg-1) in volunteers. The incidence of hypoxemia (oxyhemoglobin saturation less than 90%) and apnea (no spontaneous respiratory effort for 15 s) and the ventilatory response to carbon dioxide were evaluated. Midazolam alone produced no significant respiratory effects. Fentanyl alone produced hypoxemia in half of the subjects and significant depression of the ventilatory response to CO2, but did not produce apnea. Midazolam and fentanyl in combination significantly increased the incidence of hypoxemia (11 of 12 subjects) and apnea (6 of 12 subjects), but did not depress the ventilatory response to CO2 more than did fentanyl alone. Adverse reactions linked to midazolam and reported to the Department of Health and Human Services highlight apnea- and hypoxia-related problems as among the most frequent adverse reactions. Seventy-eight per cent of the deaths associated with midazolam were respiratory in nature, and in 57% an opioid had also been administered. All but three of the deaths associated with the use of midazolam occurred in patients unattended by anesthesia personnel. We conclude that combining midazolam with fentanyl or other opioids produces a potent drug interaction that places patients at a high risk for hypoxemia and apnea. Adequate precautions, including monitoring of patient oxygenation with pulse oximetry, the administration of supplemental oxygen, and the availability of persons skilled in airway management are recommended when benzodiazepines are administered in combination with opioids.
The Coat-A-Count solid phase 125I Fentanyl Radioimmunoassay was evaluated with respect to linearity and precision using equine urine fortified with fentanyl and then compared with a gas chromatographic/mass spectrometric method for quantification of fentanyl in urine. The RIA assay was found to be linear over the urine fentanyl concentration range of 0.25 to 7.5 ng/mL and precise with coefficients of variation (CV) ranging from 9.6 to 19.3%. The RIA calibrators, ranging in fentanyl concentrations from 0.25 to 7.5 ng/mL, and controls, at mean fentanyl concentrations of 0.46 and 1.32 ng/mL, were compared by both the RIA and GC/MS methods. The cross-reactivity with the 125I RIA test was determined for the fentanyl metabolites, norfentanyl and hydroxyfentanyl, and found to be 5% and 35%, respectively. The illicit fentanyl analogs were found to show significant cross-reactivity, ranging from 20 to 100%. The 125I RIA was compared to GC/MS quantifications of fentanyl in 35 positive and 20 negative case urine specimens.
The steady-state tissue/blood partition coefficients of fentanyl and alfentanil were determined in 13 organs and tissues in the rat. A 6-h infusion of both drugs was used in order to achieve steady-state. Blood and tissue concentrations of drugs were measured by gas-liquid chromatography. The partition coefficients of fentanyl were two- to 30-fold higher than those of alfentanil. These data were then used in a physiologic pharmacokinetic model describing the disposition of the two opioids in humans. The model predicted the plasma pharmacokinetics of these drugs in humans reasonably well. However, simulation beyond 24 h after a bolus administration showed a terminal half-life of 20 h for fentanyl, i.e., an elimination phase that has not yet been described in actual pharmacokinetic studies. In keeping with this, the volume of distribution of fentanyl in the model was also larger than expected. The simulated tissue concentration curves of fentanyl and alfentanil in humans could be used to explain the propensity of fentanyl to give secondary peaks in plasma concentration curves and the difference in effect kinetics between the two opioids. Physiologic pharmacokinetic modeling, based on measured data in small animals, can generate information that is not obtainable by empirical methods in humans.
A study was undertaken to investigate the use of fentanyl by aerosol for postoperative analgesia. Seven patients had placebo, six received fentanyl 100 micrograms and seven were given fentanyl 300 micrograms. A significant improvement in postoperative pain, as assessed by linear visual analogue scale, was achieved in the higher dose group, and in both fentanyl groups the time to alternative analgesia was significantly longer than in the control group. Serum fentanyl levels after inhalation of 100 micrograms reached a plateau around 0.04 ng/ml and after 300 micrograms at around 0.1 ng/ml after 15 minutes. Inhaled fentanyl may have a useful analgesic effect despite these low serum levels; this supports the hypothesis that the mode of analgesia from inhaled opioids may be different from that after other routes of administration. There were no adverse effects such as respiratory depression, bronchospasm, nausea or drowsiness.
The pH dependence of the aqueous solubility of morphine, fentanyl, and sufentanil was investigated at 35°C. Dissociation constants and corresponding pK
a′ values of the drugs were obtained from measured free-base solubilities (determined at high pH's) and the concentrations of saturated solutions at intermediate pH's. Morphine, fentanyl, and sufentanil exhibited pK
a′ values of 8.08, 8.99, and 8.51, respectively. Over the pH range of 5 to 12.5 the apparent solubilities are determined by the intrinsic solubility of the free base plus the concentration of ionized drug necessary to satisfy the dissociation equilibrium at a given pH. Consequently, the drug concentrations of saturated aqueous solutions fall off precipitously as the pH is raised and ionization is suppressed. Further, at low pH's the aqueous solubility of morphine increased in a linear fashion with increases in the molar strength of citric acid which was added to acidify the medium, suggesting the formation of a soluble morphine–citrate complex.
A new transdermal drug-delivery system that administers the synthetic opioid fentanyl through intact skin was evaluated for 24 hours postoperatively in eight patients who had undergone orthopedic surgery. Plasma samples were obtained over a 72-hour period for pharmacokinetic analysis in five patients. The patients were also evaluated intensively for adequacy of analgesia, frequency of nausea and sedation, and occurrence of ventilatory depression. A median lag time of 2.25 hours after application of the transdermal system was observed before the appearance of fentanyl in the blood. Median peak concentration and time to peak were 1.0 ng/ml and 22 hours, respectively. The apparent elimination of fentanyl after transdermal administration is prolonged relative to previously reported values. Absorption analysis indicates zero-order fentanyl administration, and in addition, suggests deposition of drug in an epidermal site, with the resultant prolonged absorption process giving the appearance of slow elimination. No significant toxicities were observed. Four patients required no additional analgesia. No consistent correlations among fentanyl concentration and any clinical values were observed. Transdermal administration of fentanyl appears to be a viable alternative to conventional routes of narcotic administration and warrants further study.
Fentanyl was administered intravenously and transdermally to eight surgical patients to determine the systemic bioavailability and rate of absorption of the transdermally administered drug. Serum fentanyl concentrations reached a plateau approximately 14 h after placement of the transdermal fentanyl delivery system. This plateau was maintained until removal of the system at 24 h. The decline in serum fentanyl concentrations after removal of the transdermal system had a terminal half-life of 17.0 +/- 2.3 h (mean +/- SD), considerably longer than the terminal elimination half-life seen after intravenous administration of fentanyl in the same patients (6.1 +/- 2.0 h). The rate of fentanyl absorption, predicted to be 100 micrograms/h from in vitro data, appeared to be relatively constant during a period starting 4-8 h after placement of the transdermal system until removal of the system at 24 h. The rate of absorption during this period was 91.7 +/- 25.7 micrograms/h. After removal of the transdermal fentanyl delivery system, absorption continued at a declining rate. This indicates that the long terminal half-life of serum fentanyl concentrations after transdermal system removal is due to continued slow absorption of fentanyl, probably from a cutaneous depot of drug at the site of prior transdermal system placement. At the time of removal of the transdermal fentanyl system, 1.07 +/- 0.43 mg of drug remained in this depot. Systemic fentanyl bioavailability was found to be 0.92 +/- 0.33, with no evidence of significant cutaneous metabolism or degradation by the skin's bacterial flora. The transdermal administration of fentanyl produces relatively constant serum fentanyl concentrations for significant periods of time in the postsurgical patient requiring analgesic therapy.
We have studied the transdermal absorption of tritiated fentanyl (citrate and base) and sufentanil citrate.
Approximately 50 µg of drug in water was applied to the forearm skin of volunteers (5 subjects for fentanyl citrate and base, 6 for sufentanil). When the water had evaporated the site was covered with an occlusive dressing. Total urine collections were carried out for 96 h in 12 h periods. At 24 h the dressing was removed and skin removed with serial applications of adhesive tape. The radioactivity in the urine and on the tape was measured in a scintillation counter.
Urine recovery expressed as a percentage of the absorbed dose was 17.9±1.9% for fentanyl citrate, 20.5±5.6% for fentanyl base, and 22.5±2.5% for sufentanil. In one subject who ran 10 miles with a sufentanil patch in situ the recovery was 52.3%. The systemic availability of fentanyl by this route is approximately 30% of that found using the intravenous route.
An accidental overdose fatality resulting from the intravenous injection of Sublimaze (fentanyl) is presented. Fentanyl was extracted from postmortem specimens by a basic extraction procedure. Benzene was used as the extraction solvent and alfentanyl as the internal standard. The drug was quantitated by electron impact gas chromatography/mass spectrometry in the selected ion monitoring (SIM) mode. Fentanyl concentrations were, blood, 4.0 micrograms/L; urine, 13.0 micrograms/L; liver, 9.7 micrograms/kg, and kidney, 8.6 micrograms/kg.
High-dose fentanyl anesthesia is widely used in cardiac surgery. Its immediate side-effects are well known. However, its late adverse effect manifested by extreme truncal rigidity, decreased chest wall compliance, hypoventilation, respiratory acidosis and hemodynamic instability is not sufficiently appreciated. Of 380 patients who underwent aortocoronary artery bypass under high-dose (100 micrograms/kg) fentanyl anesthesia, 29 (7.6%) developed the sudden onset of extreme thoracic and abdominal rigidity, leading to respiratory depression 2 to 6 h postoperative, after an apparently normal recovery from the anesthesia. In 15 patients, a high plasma level of fentanyl (5.2 to 7.8 ng/ml) correlated with the clinical events. Administration of naloxone or a muscle relaxant rapidly reversed this late complication of fentanyl, thought to be due to re-entry of fentanyl into plasma from deposits in adipose tissue, muscle and the GI tract, leading to a secondary peak in plasma fentanyl. It is more likely to be encountered when hypothermia, rewarming, and acidosis occur in the postoperative period. Awareness of this life-threatening complication is critical in patients undergoing surgery with fentanyl anesthesia.
• A delayed effect of fentanyl used for anesthesia may be respiratory distress several hours after surgery. The findings are muscular rigidity, fall in chest wall compliance, hypoventilation, respiratory acidosis, and hypotension. In the past, to our knowledge, this complication was exclusively reported in patients undergoing cardiac surgery, when large fentanyl dosages are employed. This article describes three general surgical patients in whom respiratory distress developed three to five hours following colon surgery when a moderate dose of fentanyl citrate, 55 to 75 μg/kg, was used. Initially, all patients had a normal recovery from anesthesia. Later, respiratory distress was successfully treated with a fentanyl antagonist and ventilatory assistance. This delayed toxic phenomenon is thought to be due to the reentry of fentanyl into plasma from deposits in adipose tissue, muscle, and the gastrointestinal tract, leading to a secondary rise in the plasma concentration. It is more likely to be encountered when hypothermia, rewarming, and acidosis are present in the postoperative period. This life-threatening complication is treacherous, since it may occur when the patient has been transferred to the surgical ward and is less closely monitored.
(Arch Surg 1988;123:66-67)
The inter- and intrasubject variability in blood concentration-analgesic response relationship for fentanyl were investigated using the technique of patient-controlled analgesia (PCA) in 30 consenting patients scheduled for surgical procedures involving an abdominal incision (15 upper and 15 lower abdominal incisions). All patients had a thiopental, nitrous oxide/oxygen, pancuronium anesthetic with 200 microgram fentanyl intraoperatively. Postoperative pain relief was provided with fentanyl from a Janssen On-Demand Analgesic Computer (ODAC) set to provide a basal infusion rate of 20 microgram/hr, a bolus "demand" dose of 20 microgram, and a lockout period of 5 minutes. Frequent blood samples were collected immediately before patients demanded doses, and these were taken as an estimate of the minimum effective concentration (MEC). A mean of 22 samples (range 12 to 45) were collected per patient over a mean study duration of 50 hours (range 24 to 72). The patients required larger hourly fentanyl doses in the first 6-hour period (83.9 +/- 30.1 microgram/hr) than in any other 6-hour period (mean values varied from 37.3 to 63 microgram/hr). The mean (+/- SD) hourly fentanyl dose rate and total cumulative dose were 55.8 +/- 22 microgram/hr (range 28.8 to 136 microgram/hr) and 2739 +/- 1191 microgram (range 900 to 6260 microgram), respectively. The mean (+/- SD) MEC was 0.63 +/- 0.25 ng/ml (five-fold range from 0.23 to 1.18) and the mean intrapatient coefficient of variation in MEC was 30.2% (range 16 to 46%). The MEC values remained relatively constant in all patients over the 48-hour study period.(ABSTRACT TRUNCATED AT 250 WORDS)
Minimum effective fentanyl concentrations (MEC) were determined in 230 ASA I-III patients undergoing a variety of elective surgical procedures under balanced anesthesia, and in 40 patients recovering from comparable operations and anesthesia during postoperative intravenous self-administration of fentanyl (demand dose 34.5 micrograms) by means of the On-Demand Analgesia Computer. Following induction of anesthesia with fentanyl 4 micrograms/kg, repetitive fentanyl reinjections (0.1-0.2 mg) were given intraoperatively whenever systolic blood pressure or pulse rate increased to more than 20% of preinduction values, resulting in an intraoperative fentanyl consumption of 4.2 +/- 1.2 micrograms/kg/h. Duration of postoperative patient-controlled analgesia (PCA) was 20.2 +/- 4.3 h during which time 15.5 +/- 12.9 demands per patient were registered, resulting in a postoperative fentanyl consumption of 0.46 +/- 0.35 micrograms/kg/h. MECs appeared to be log-normally distributed (intra-operative median 2.6 ng/ml, range 0.2-36.6; postoperative median 1.2 ng/ml, range 0.2-8.0). Mean intra- and interindividual variability in MEC was 37% intraoperatively or 27% postoperatively, and 68% or 63%, respectively. There was no obvious correlation between postoperative fentanyl consumption or individual mean MEC and analgesic efficacy, which was generally described as superior to conventional pain treatment. Individual MECs increased gradually during anesthesia (mean slope 0.0191 ng/ml/min) but decreased under PCA conditions (-0.0008 ng/ml/min); difference not significant. While the postoperative decrease could be explained by diminishing pain intensity during the observation period, the slight intraoperative increase is discussed as acute tolerance rather than as accumulation. It is concluded that repetitive fentanyl injections as indicated by clinical needs will not lead to relevant accumulation in serum, and that analgesic therapy should be individualized both intra- and postoperatively.
SUMMARY We have investigated the use of constant-rate delivery of fentanyl by i.v. and transdermal routes for the treatment of pain
after major surgery. Forty-five males, ASA I–III, received in a doubleblinded fashion either placebo (n = 6) or fentanyl (n
= 39) i.v. at one of four dose rates (25, 50, 100 or 125 μg h−1). Stable serum concentrations of fentanyl were produced by the end of surgery and were maintained for a total of 24 h. Calculated
clearance of fentanyl was 1.05±0.38 litre min−1 and was not related to weight or age. Both the 100- and 125-μg h−1 dose rates produced significant analgesic efficacy as assessed by postoperative morphine requirements. Mean serum concentrations
of fentanyl in these groups were 1.42±0.14 (SD) and 1.90±0.30 ng ml−1, respectively. One of 10 patients receiving fentanyl 100 μg h−1 and three of nine patients receiving 125 μg h−1 had evidence of respiratory depression. Eight additional patients were treated with a transdermal drug delivery system containing
fentanyl (TTS-fentanyl). Steady-state serum concentrations in this group were 2.15±0.92 (SD) ng ml−1. Postoperative morphine requirements were minimal (< 0.5 mg h−1) and PaCO2 remained acceptable in all patients. Serum concentrations of fentanyl increased slowly (15 h to plateau) and decreased slowly
(apparent half-life, 21 h). We conclude that delivery of analgesic doses of fentanyl is feasible by the transdermal route.
Selected ion monitoring gas chromatography/mass spectrometry was employed to quantitate fentanyl in blood, liver, and kidney
from a death attributed to a fentanyl overdose. The concentration of fentanyl was 3 ng/mL blood, 11 ng/g liver and 14 ng/g
kidney.