Specific model improvements that could enhance the accuracy are discussed in section Mechanistic Modeling. However, for this particular discrepancy during the later stage of the drug uptake process, a particular factor is likely to be responsible in part. Due to the high diffusion coefficient of the patch, the concentration in the patch is very uniform and almost equals that at the patch-skin interface.
As such, the main concentration gradients occur over the skin, as predicted in-silico. Over time, the concentration in the patch decreases, which leads to a reduced gradient over the skin.
The steep decrease in the flux in the experiments could indicate that also a concentration gradient inside the patch could be present.
This would be caused by a lower diffusion coefficient in the patch than currently used in the simulations. The path length for the molecules to travel through the skin would progressively increase over time, hence reducing the flux more than based on a concentration gradient over the skin alone.
Perhaps this type of experiment in an aqueous medium leads to too high diffusion coefficients compared to when the patch placed on the skin. If the diffusion in the reservoir holding the drug should be restricted more, a better agreement with experiments over the entire uptake process could likely be obtained but this hypothesis should be further explored. The current discrepancy of the model with the experimental data leads to a lower predicted amount of fentanyl than in reality.
As a result, the targeted pain relief, as predicted from the in-silico drug dose, will not be reached in reality. However, the patient will certainly not get a higher drug dose than predicted by the model. The model thereby provides a conservative drug uptake estimate, which is safe for the patient.
Therefore, a 1D transport model can be used as a viable alternative for the 3D model. The drug uptake from the simulated transdermal patch base case is compared with that of commercial TDDS in Figure 4.
The delivery rate is rather constant, but there is a slight decline due to the reduction of reservoir concentration, which is the driving force for drug transport.
Commercial patches, however, only report the targeted steady-state value that does not reflect this slight decline in flow rate, because these TDDS are designed to deliver the drug at a nearly constant rate. The reason is a different patch design or material composition.
In summary, our mechanistic model produces uptake rates and kinetics in a similar range as commercial products. Combined with the validation study results, this tool is reliable for product design and optimization. Figure 4 Drug flow as a function of time for drugs released by the patch g pt,rel , for drugs taken up by the blood flow g bl,up for the base case and commercial fentanyl patches.
The results of an infinite reservoir are also shown. The relative sensitivity of the flux across the skin into the blood g bl,up to the input parameters is shown in Figure 5A. These results quantify the parameters that affect the most the predicted drug uptake, and how this sensitivity changes over time.
The total amount of drugs taken-up after a certain period is shown in Figure 5B. Concerning the magnitude of the sensitivities, the data show the largest sensitivity for the model parameters that describe the stratum corneum. The partition coefficient has the largest overall impact of all model parameters.
The thickness and the diffusion coefficient have similar sensitivities due to their comparable role in the conservation equation [Eq. There is a distinct temporal sensitivity to the different model parameters, especially the thickness and diffusion coefficient of the stratum corneum and the initial drug concentration in the reservoir.
This temporal sensitivity originates from the transient nature of the uptake process. Initially, loading of the drug in the skin occurs first 10 h , which involves drug storage and transport through the skin. After this initial period, the sensitivity is more constant over time. The highest temporal sensitivity occurred for the initial drug concentration, with a sensitivity to the mass flux that reduces to only a few percent after the first 10 h Figure 5A. For designing drug delivery systems and therapy, the initial drug concentration in the patch is an important factor, and also comes into play when replacing the patch.
In summary, uncertainty in model parameters impacts the solution. Still, this effect is smaller than the disturbance itself i. Nevertheless, the solution is particularly sensitive to the model parameters of the stratum corneum, especially the partition coefficient, so these parameters must be known as accurately as possible. The drug release and uptake kinetics from the patch into the skin are presented in Figure 6 for the base case, specifically by analyzing the contributions to diffusion and storage processes including partitioning.
These data display what the temporal delay is between drug release and uptake, and how much drugs are stored in the different skin layers over time. In parallel to diffusive transport, drugs accumulate in the skin during the first 6—7 h.
After that, the drug primarily diffuses through the skin, and the stored amount remains rather constant. The stored drug amount in the skin is, however, only a fraction of the total drug amount initially present in the patch, with a maximal value of 0. Due to the decreasing drug concentration in the patch a finite reservoir , the uptake flux slowly decreases over time, simply because the concentration gradient decreases. Figure 6 A Amount of drug stored in the epidermis [m ep,stor t ] and patch [m pt,res t ], and cumulative amounts of drugs released by the patch m pt,rel t and taken up by the blood flow m bl,up t as a function of time for the base case.
The initial amount of drugs is also shown. B Corresponding flux released by the patch into the epidermis g pt,rel and taken up by blood g bl,up as a function of time, where one insert shows the percentage for the maximal value. The patch is depleted by half of its initial amount after h almost 8 days. Typically, fentanyl patches are replaced every 72 h or 3 days e. However, transdermal patches are designed to deliver the drug at a controlled rate to achieve a constant blood plasma concentration rather than delivering the entire amount of drug and depleting the reservoir Perrie and Rades, Therefore, the concentration in the patch cannot reduce too much, as this would imply the driving force for drug transport, i.
As such, a significant drug concentration should still be present when removing the patch, to guarantee a rather constant drug flow McEvoy et al.
Larsen Larsen et al. For comparison, the results of an infinite reservoir with high diffusive drug transport are also shown in Figure 6. As expected, a constant flux is reached after an initial uptake period. In other words, there is a linear increase in the drug amount taken up with time. Ideally, TDDS are designed to deliver drugs at a constant rate. The resulting constant fentanyl flux 1. The finite reservoir deviates from this constant rate.
Additionally, Supplementary Material 3 shows that the differences with a 3D model are limited, and the anisotropic transport properties between transverse and longitudinal direction have a limited impact on the evaluated patch width.
We compare the high spatiotemporal resolution data from the simulations against typical data obtained in TDDS experiments. This endeavor identifies additional insights and benefits gained from mechanistic modeling. In experiments, drug uptake is typically measured using a Franz diffusion cell at discrete time intervals e. Even if the total amount of drug taken up is correct, such temporal averaging masks local flux peaks in time and the associated maxima in concentrations.
This information is essential because concentrations of specific drugs that are too high may induce skin irritation Hogan and Maibach, ; Brockow et al.
The discrepancies induced by such temporal averaging are quantified in Figure 7 , as derived from our simulation data. The average flux for different time-averaging intervals is calculated by grouping our simulation results over specific intervals because these can be derived from the fluxes at each point in time.
However, this accuracy strongly depends on the process kinetics during that timeframe. Simulations also allow researchers to mimic experimental conditions in a deterministic way, without suffering from biological variability and the resulting uncertainty.
Figure 7 Flux taken up by the blood as a function of time for 3 time-averaging intervals, based on simulation data. The horizontal dashed lines indicate the time range over which the averaging took place, i. To further illustrate the added spatiotemporal insights on drug transport obtained by simulations, the vertical concentration profiles through the patch and skin are shown in Figure 8. The experimental counterpart to obtain such profiles would be tape stripping Lademann et al.
This process, however, only extracts the profiles at a single point in time, where typically steady-state conditions are targeted. The obtained 1D spatial resolution by tape stripping is in the micron range, but is strongly dependent on the anatomical site, age, stratum corneum thickness, number of cell layers, and corneocytes, among others Lademann et al.
Contour plots of concentration and potential from the simulations are shown in Figure 9. Partitioning is indicated by the much higher concentrations of the moderately lipophilic drug in the stratum corneum compared to the viable epidermis. These large concentration jumps challenge the numerical stability of the simulation, which is why the conservation equations were solved against the drug potential instead of drug concentration in this study.
Figure 8 Concentration profiles at different points in time as a function of the height of the model z-direction, scaled with the epidermal thickness in the vertical centerline z-axis of the patch for the base case: A entire model logarithmic scale , B reservoir, C stratum corneum, D viable epidermis.
Different scaling is used in A, B to improve clarity. Note that the maximal range 80 kg m -3 is not depicted. After initially loading the epidermis with the drug, a quasi-steady-state diffusion process develops, with the typical linear concentration distribution over each epidermal layer Figures 8C, D. The concentration reduction in the patch Figure 8B , however, still induces a slight temporal shift in the concentration profiles in the epidermis Figures 8C, D.
The simulations enable us to analyze what occurs within the epidermis when the fentanyl patch is removed after the recommended h period. This analysis is possible because simulations can quantify volume-averaged drug contents as well as surface-averaged fluxes. In Figure 10 , the drug uptake amount in the blood, the corresponding flux, and the drug storage in the skin are shown as a function of time.
A very small drug amount was stored in the skin 0. Because only this amount can further diffuse into the blood once the patch is removed, the drug amount that is taken up steeply decreases after removal. However, it still took approximately 24 h before this residual amount diffused from the skin to the blood.
Figure 10 A Amount of drug stored in the epidermis [m ep,stor t ] and the cumulative amount of drugs taken up by the blood flow m bl,up t as a function of time for the case where the patch is removed after 72 h. B The corresponding flux that is taken up by blood g bl,up as a function of time. The impact of the anatomical location of the drug reservoir on the human body was also investigated. The absorption of drugs through the skin differs in different body locations due to a different thickness of the stratum corneum or the presence of the hair follicles Feldmann and Maibach, In Figure 11 , the amount of drug uptake is given for three-body sites that differ in terms of epidermal thickness.
The HUT section Metrics is also indicated for each body location, as calculated based on the curves with average thickness. The HUT for the base case was h. Figure 11 Cumulative amount of drug taken up in the blood as a function of time for the forearm A , shoulder B , buttock C epidermal thickness averaged for all body sites D. For comparison, the results of the base case are also depicted.
The thickness of the epidermis d ep and half-uptake time HUT are indicated as well.. The largest drug uptake was observed on the shoulder, while the smallest was obtained for the forearm.
The results for the average epidermal thickness over all the body sites agree with the base case. Interpatient variability in the stratum corneum and epidermis thickness directly manifested itself in drug uptake rates. Clinically, this finding implies that specific patients can have blood serum concentrations that can be too high toxic or too low to be effective for that specific patient.
This interpatient variability for a specific anatomical location induces significant variability on the drug uptake results. This spread makes it challenging to distinguish significant differences between anatomical locations in clinical experiments. In contrast to the present study, specific previous studies reported limited differences in fentanyl uptake between the anatomical location Roy and Flynn, ; Larsen et al. The impact of patient age on drug uptake kinetics was investigated by calculating variations in the stratum corneum thickness with age via Eq.
In Figure 12 , the drug uptake and flow rate are given for different age groups [as previously defined Boireau-Adamezyk et al. The current mechanistic model can even be used to define an age-specific dosage systematically. Figure 12 A Cumulative amount of drug taken up in the blood as a function of time for different age categories.
The results of the average age of each group are shown, as well as the minimal and maximal ages. B Drug flow taken up by the blood as a function of time for different age groups and commercial fentanyl patches.
For both A, B the gray band indicates the entire range of ages that is evaluated 18—70 years. Furthermore, the time before the minimal effective concentration is reached in the blood differs with age.
As an example, it took 23 h to uptake 0. Our simulations showed that, with aging, the patch delivered drugs more slowly and less potently. Mechanistic simulations enable researchers to quantify this difference deterministically and theoretically, without introducing additional statistical uncertainty concerning interpatient variability.
We explored how the reservoir width, and thus the contact surface area affected the released flux. For normal TDDS, the reservoir is much wider than the epidermal thickness, which is the longitudinal transport pathway for the drugs.
This phenomenon leads to unidirectional transport. Hence, the 3D edge effect induced by transverse diffusion at the edges of the patch is negligible. This examination aimed to identify whether a reservoir with a smaller contact surface area released drugs faster and at a higher rate than a standard patch.
Since transport will occur in 3D in the case of patches with a smaller contact area, this transverse diffusion could induce higher fluxes. In Figure 13 , the released flux surface 2 is shown as a function of time for all reservoir surface areas for finite and infinite reservoirs. Figure 13 Flux released by the patch into the skin g pt,rel , surface 2 as a function of time for different reservoir sizes L pt , so contact surface areas, for A finite reservoir, B infinite reservoir.
Figure 14 Flux released by the patch into epidermis after 72 h g pt,rel for the infinite reservoir as a function of the reservoir size L pt , so contact surface area, scaled by the epidermal thickness d ep. In the schematics, dimensions of the patch and skin thickness are to scale, but the skin width is not to scale. The flux leaving the reservoir is dependent on the size so contact surface area of the drug reservoir in contact with the skin, for both finite and infinite reservoirs.
For the finite reservoirs, the depletion of the smaller reservoirs causes the flux to decrease sharply over time. This depletion can, however, be mitigated by increasing the thickness of the reservoir d pt or by connecting all small reservoirs to a large bulk reservoir. The infinite reservoirs evolve to a steady-state, a condition that is more convenient for comparison of the reservoir contact surface area.
Once the size L pt enters the submillimeter range, or the patch size goes below approximately 10 x d ep , the flux increases to more than double of that of a conventional patch base case.
This phenomenon occurs because the drug can diffuse in three dimensions instead of predominantly one direction for the large reservoirs. Furthermore, the transverse diffusion coefficient of the stratum corneum is a few orders of magnitude larger than the longitudinal one [ Rim et al.
Thereby, for smaller contact surface areas, longitudinal and transverse diffusion occur, a process that induces a higher flux at the contact interface.
This edge effect is illustrated in the contour plots presented in Figure Note that these factors decrease to 3 and 18, respectively, when the transverse diffusion coefficient would just equal the longitudinal one results not shown. This data implies that transverse diffusion is a key parameter for the large observed differences, partially due to the higher transverse diffusion coefficient of the stratum corneum layer, especially when the reservoir is not very wide compared to the skin thickness.
The amount stored in the skin is, in all cases equal to, or smaller than the base case. Note that the smallest reservoirs are of the same size as the corneocytes Figure 1 but still much larger than the lipid bilayer thickness [approximately 10 1 nm Das and Olmsted, ]. As such, the drug concentration contours could depend to some extent on where the reservoir is precisely placed, relative to the corneocyte or lipid bilayer at the surface.
This can be visualized with a mesoscale model Figure 1. However, in the current lumped approach with anisotropic diffusion in the SC layer, we receive an average drug uptake profile. This is justified if we assume that for a complete patch, the reservoirs are randomly located on the skin by which the average uptake we simulate is still representative.
Note that the trend we see for these very small reservoirs is already present for the reservoirs that are much larger than the corneocytes Figure This implies that smaller reservoirs progressively take more benefit more of the transverse diffusion, compared to larger reservoirs, to increase the drug uptake flux. Figure 15 Color contours of drug concentration over the skin for different sizes of the reservoir for simulations with an infinite reservoir after 72 h, so when a steady-state is reached.
Note that the maximal range is not depicted 80 kg m -3 , and only one-fourth of the patch-skin system shown due to symmetry. Such mechanistic modeling provides several advantages compared to the analytical solution of the diffusion-driven drug uptake process Rim et al. Such analytical solutions enable to calculate drug dose taken up for several drugs, based on their diffusive properties of the skin. Mechanistic modeling is, however, required to target more complex situations, for example, when considering the skin as a multi-layer structure stratum corneum, viable epidermis or when the patch is replaced so if the boundary conditions change over time.
Compared to the current study and state of the art Table 1 , further advancements should be pursued to enhance the realism and accuracy of transdermal drug delivery predictions in terms of 1 the modeled transport processes, 2 the targeted drug delivery system, 3 numerical modeling, and 4 the model parameters. These future targets for model development are detailed below. Concerning transport processes, the physical adsorption of molecules or chemical binding should be included to enhance accuracy.
For fentanyl, bioavailability through the skin is very high [e. Thus, some of the fentanyl does not reach the systemic circulation, due to absorption in the epidermis or by chemical changes. Including these mechanisms in mechanistic models is not yet a standard practice Yamaguchi et al. The current mechanistic model for transdermal drug delivery is built up for first-generation systems Prausnitz and Langer, Thereby, in addition to fentanyl, it can also be calibrated for lipophilic drugs with a small molecular weight, for example, ibuprofen Tombs et al.
For next-generation systems Bartosova and Bajgar, ; Lee et al. These systems aim to enhance skin permeability by increasing the driving force for drug uptake via chemical permeation enhancers, iontophoresis, or by disrupting the stratum corneum using microneedles or thermal ablation Bartosova and Bajgar, Furthermore, when including the dermis in the model Naegel et al.
Modeling the dermis without drug extraction by blood flow will underpredict the drug uptake rate. The impact of including the dermis in the modeled system configuration is illustrated in Supplementary Material 4 Figure S2 , where the impact of different dermis thicknesses on diffusive drug transport is illustrated, so without modeling blood flow. Due to the relatively large dermis thickness and volume, modeling only diffusive transport overpredicts the amount of stored drug and transverse spreading found in specific studies Selzer et al.
For an infinite reservoir under steady-state conditions, where Fickian diffusion would predict a constant flux, swelling will introduce a time-dependency into the flux Perrie and Rades, The swelling or shrinkage of the patch could also be considered Rim et al. Finally, diffusion and partition coefficients that are a function of drug concentration rather than constant values should be used, especially if there are large variations for the drug of interest. This alteration significantly changes its equilibrium distribution.
Their importance should be assessed on a case by case basis. Concerning the modeled delivery system, finite reservoirs should always be preferred over infinite reservoirs, which are currently still commonplace Table 1. For finite reservoirs, the gradient, therefore the driving force, will decrease, a phenomenon that makes delivery at a constant rate more challenging Figure 6. For this reason, controlled drug delivery systems were designed to alleviate the decreasing concentration gradient [e.
Future models should also include the dermis. This inclusion is essential to evaluate the drug share taken up by the blood versus the amount of the drug that diffuses into and is stored in the thick dermis.
This factor will affect total bioavailability and uptake kinetics. In this study, the storage in the dermis was assumed small compare to the amount of drug taken up via the dermis in the blood flow, due to the large bioavailability of fentanyl. If the dermis is included in the computational model, it is essential to include the blood flow in capillaries and vessels and to adjust this blood flow as a function of patient age and activity level, among others Simmons et al.
Another reason to include the dermis is that the current boundary condition imposed at the viable epidermis surface 1 , namely a zero concentration, has a certain limitation. This condition is valid in experimental setups with Franz diffusion cells, but it can be disputed for a real human tissue. Here, the concentration profile at the viable epidermis will result from the trade-off between diffusion and uptake by the blood flow. Finally, the mechanistic model should be linked to a pharmacokinetic model that relates the uptake amount to the metabolization process in the body to obtain the final blood plasma concentration.
Concerning numerical modeling, there were large discontinuities in concentration over the skin layers due to partitioning. To improve numerical stability and accuracy, it is advised to solve for a dependent variable other than concentration, as was performed in the present study using drug potential.
Concerning the model parameters, the diffusion and partition coefficients are rarely measured explicitly before modeling using a separate in vitro experiment. Instead, data from the literature are utilized, often even from other drugs with similar molecular weight and lipophilicity Rim et al. Alternatively, data are also fitted Rim et al. Obtaining a good agreement, in this case, is not surprising and can mask missing physical processes within the model.
Therefore, one cannot claim the model is validated, but rather it should be considered calibrated. This procedure to obtain model parameters is not necessarily discouraged, but one cannot use the same dataset for model fitting and experimental comparison. Selzer et al. This approach is certainly viable, but the resulting model parameters still led to differences in the experiments. The impact of aging on transdermal drug delivery was considered by changing the stratum corneum thickness.
For a year-old patient, the drug taken up by the blood was lower, and the maximum peak flow of the drug occurred later in time than for an year-old patient. This in-silico data analysis quantified the dose delivered for differently aged patients for a specific drug concentration in the patch. Moreover, the slight time shift in peak drug flow is also helpful for defining the time window where patients of different ages may be more susceptible to developing side effects.
This information enables more precise monitoring and prevention of serious side effects. This would be a step forward compared to current conventional transdermal fentanyl therapy. Where the initial dose so patch size is being estimated based on previous daily doses of oral morphine for the patient McPherson, , with applying the patch transdermally and replacing it every 72 h Muijsers and Wagstaff, These features would allow a tailored treatment and a constant delivery rate below defined thresholds Lee et al.
Additional age-related changes in the stratum corneum structure, such as a decrease with lipid content and its composition Rogers et al. There are several challenges with designing such tailored devices or therapy for transdermal drug delivery and implementing then into the clinics. The most straightforward solution that could be implemented the most swiftly would be to use conventional transdermal therapy based on existing fentanyl patches.
The most optimal therapy with respect to the initial concentration in the patch, the amount of time it should be applied currently 72 h , and the location where it should be applied could be determined per age category. This means that a clinician could use the mechanistic model to decide which patch to use e.
Before undertaking clinical trials in vivo, a detailed in vitro study is still required. The model and its transport processes were validated already using Franz diffusion cells section Validation.
Nevertheless, the findings with respect to age and anatomical location need to be confirmed experimentally to further consolidate the findings out of the present study. Such an in vitro study is also an essential next step to further widen the possible use of the numerical model to help designing fentanyl therapy.
In reality, patients within this individual category will also have a certain variability in skin build-up, so drug uptake. We report successful management of such a case utilizing whole bowel irrigation along with intravenous push and continuous infusion naloxone. Fentanyl, a potent phenylpiperidine opioid agonist available as a transdermal patch, carries a black box warning cautioning health care providers on both the potency of the product and the potential for abuse and diversion [ 1 ].
Numerous consumer Internet websites describe means for abusing fentanyl patches, such as smoking, chewing, freezing, or intravenous injection of the gel reservoir [ 2 , 3 ].
In , Goldberger and colleagues presented data from the state of Florida which found fentanyl as the cause of deaths [ 4 ]. Although anecdotal reports exist, there is little published in medical literature regarding oral intoxication of fentanyl patches [ 5 — 8 ]. We describe both the presentation and management of a patient who ingested two fentanyl patches. A year-old white male was brought to the emergency department ED via emergency medical services EMS for a toxic ingestion.
The patient was in a verbal altercation around with his ex-wife, resulting her calling the police department. After discovering law enforcement was en route, his ex-wife witnessed the patient chewing and ingesting two illegally purchased 50 micrograms per hour transdermal fentanyl patches, along with 6—8 milligrams of alprazolam. EMS found the patient to be nonresponsive to verbal or physical stimuli, bradycardic, and with miotic pupils.
Two milligrams of intravenous naloxone were administered by EMS, which resulted in opioid reversal and arousal of the patient. The patient was subsequently transferred to our ED with findings of altered mental status, obtundation, and drowsiness. The patient admitted to regular use of methamphetamine, opioids, and benzodiazepines and had a past medical history bipolar disorder for which he took no medications.
His review of systems was negative, except for the dizziness, drowsiness, and altered mental status, and admission physical examination was unremarkable. Initial chemistry, liver function tests, and complete blood count were all within normal limits.
A urine drug screen was negative for opioids, but positive for amphetamines and benzodiazepines. Serum ethanol, acetaminophen, and salicylate levels were all negative. A serum fentanyl level was not obtained. The patient arrived in the ED at Upon arrival, the patient was stabilized and assessed. At , a naloxone drip 8 micrograms per milliliter in 0.
Additionally, whole bowel irrigation with polyethylene glycol via nasogastric tube was initiated secondary to concerns for ingested patches creating a depot-like effect. The patient had one bowel movement in the ED no documentation that patches or remnants were passed and remained hemodynamically and neurologically stable until transfer to the medical intensive care unit at approximately that evening.
His naloxone drip was titrated down to 0. He did not receive any additional naloxone after this point. In total, he received approximately 15 milligrams of naloxone over these two days. He remained cardiovascularly and neurologically stable throughout his stay in the medical ICU, was subsequently downgraded to the medical floor on hospital day 3 48 hours after admission , and discharged from the hospital on day 4 at Multiple ingestions of fentanyl patches have been reported, with outcomes ranging from transient symptoms of overdose e.
Van Rijswijk and Van Guldener described the case of an year-old male with a history of multiple myeloma, osteoporosis, and delirium who was found chewing on a fentanyl patch [ 5 ]. After administration of naloxone 0. Thomas and colleagues published a case report of a year-old male with known drug abuse, including hospitalization for drug overdose, who died subsequent to oral ingestion of fentanyl patches [ 6 ]. Upon autopsy, the decedent had three pieces of fentanyl patches in his stomach.
Further history reveals that the decedent commonly chewed, sucked on, and swallowed fentanyl patches to obtain a high. Lastly, Woodall and colleagues reported a case series of seven deceased patients in whom oral administration of a fentanyl patch was suspected to have contributed to their death [ 7 ].
Decedents ranged in age from 20 to 51 years and had oral and transbuccal administration of a patch based on witness reports or evidence of patch residue in the oral cavity. More recently, Carson and colleagues presented a case of a year-old white male who died in the ED after chewing and aspirating a transdermal fentanyl patch.
On autopsy, the decedent had a beige foreign body later identified as the transdermal device lodged in the mainstem bronchus, and postmortem toxicological analysis revealed a serum fentanyl level of 8.
Due to the typical return time on these types of labs, we felt an admission fentanyl level would be of little benefit to the medical team three days later. Therefore, as alluded to in published case reports, the time fentanyl stays in contact with the oral mucosa directly translates to the systemic absorption and the severity of the overdose.
The fentanyl in the patch diffuses through the skin and depots in the adipose tissue and provides sustained pain relief. Very hairy skin may need to be shaved locally before applying the patch. The efficacy of absorption of the fentanyl is dependant on the skin temperature and the availability of adequate adipose tissue. Therefore some patients who are cachetic or hypothermic may not get adequate pain relief. In contrast patients who are febrile may absorb more of the medication thus necessitating either a dose decrease if they are experiencing undue side effects or a need for the patch to be changed as often as every 48 hours.
Therapeutic blood levels are not reached for hours after patch application.
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