Forensic Science International 251 (2015) 195–201

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Postmortem distribution of trazodone concentrations Iain M. McIntyre a,*, Phyllis Mallett a, Robert Stabley b a b

Forensic Toxicology Laboratory, County of San Diego Medical Examiner’s Office, 5570 Overland Ave., Suite 101 San Diego, CA 92123 USA County of San Diego Medical Examiner’s Office, 5570 Overland Ave., Suite 101 San Diego, CA 92123 USA

A R T I C L E I N F O

A B S T R A C T

Article history: Received 3 December 2014 Received in revised form 30 March 2015 Accepted 4 April 2015 Available online 17 April 2015

Non-toxic postmortem trazodone tissue (liver) concentrations have not been previously described. Liver trazodone concentrations were compared to peripheral blood and central blood concentrations in 19 medical examiner cases. Postmortem blood specimens were initially screened for alcohol and simple volatiles, drugs of abuse, and alkaline drugs. Trazodone, when detected by the alkaline drug screen, was subsequently confirmed and quantified by a high performance liquid chromatography procedure. Reanalyses showed that there may be degradation of trazodone in postmortem blood stored at 4 8C. There was, on average, about a 20% decrease in samples stored up to eight months. These data suggest that postmortem trazodone peripheral blood concentrations may be considered non-toxic to at least 1.0 mg/L with liver concentrations to at least 2.2 mg/kg. Overall, trazodone concentrations ranged from 0.08– 6.1 mg/L in peripheral blood, 0.07–7.1 mg/L in central blood, and 0.39–26 mg/kg in liver. The median trazodone central blood to peripheral blood ratio was 0.98 (N = 19). The liver to peripheral blood ratios showed a median value of 2.8 L/kg (N = 18). Given that a liver to peripheral blood ratio less than 5 L/kg is consistent with little to no propensity for postmortem redistribution, these data demonstrate that trazodone is unlikely to show significant redistribution. ß 2015 Elsevier Ireland Ltd. All rights reserved.

Keywords: Trazodone Peripheral blood Central blood Liver Postmortem redistribution

1. Introduction Trazodone (Desyrel1, Molipaxin1, Oleptro1, Trazamine1, Azona1 Deprax1, Depyrel1, Desirel1, Sideril1, Thombran1, Trazodil1, Trazolan1, Trazorel1, Triticum1, Trittico1) is a triazolopyridine derivative used as an antidepressant agent since 1980 [1,2]. It is structurally unrelated to the tricyclic or tetracyclic antidepressants. As the hydrochloride salt, it is available in 50–300 mg normal-release capsules or tablets, 150–300 mg extended release tablets, and 50 mg/5 mL syrup. The usual daily dose for adults ranges from 150 to 400 mg in single or divided doses [1]. The maximum recommended daily dose is 600 mg [2]. In clinical investigations, therapeutic plasma concentrations of trazodone following a dose of 100 mg were reported to peak at 1.1 mg/L by 2 h [3]. Following a single oral dose of 150 mg, a mean peak plasma concentration of 2.0 mg/L was attained by about 2 h [4]. Trazodone is readily absorbed after oral administration, and it is metabolized by hydroxylation and oxidation [2]. The estimated half-life of elimination is generally reported at 3–7 h [5]. Steady state serum trough serum concentrations have been reported to

* Corresponding author. Tel.: +1 858 694 2907; fax: +1 858 495 5383. E-mail address: [email protected] (I.M. McIntyre). http://dx.doi.org/10.1016/j.forsciint.2015.04.009 0379-0738/ß 2015 Elsevier Ireland Ltd. All rights reserved.

average 0.7 mg/L after 12 days with dosing of 25 mg three times a day [6], and from 0.7 to 1.6 mg/L following 400 mg daily [7]. Steady state plasma trazodone concentrations ranged from 0.50 to 1.2 mg/ L in depressed patients [8], and concentrations from 0.24 to 4.9 mg/L were reported in elderly depressed patients treated with an average dose of 354 mg [9]. Adverse effects of trazodone at higher dose levels include central nervous system depression, with symptoms of nausea, drowsiness, confusion, dizziness, fatigue, incoordination, dry mouth, and headache [5]. Overdosage can cause hallucinations, delusions, slurred speech, seizures, respiratory arrest, and death [5]. Serotonin syndrome may occur when trazodone is used in combination with other serotonergic agents such as nefazodone and venlafaxine [10,11]. However, plasma trazodone concentrations of 15–19 mg/L were observed in two overdose cases who exhibited only drowsiness and ataxia [12]. Postmortem concentrations, on the other hand, have been described after an overdose with 2–4 g trazodone at a blood concentration of 15 mg/L, and liver 57 mg/kg [13]. Two other cases were found to have concentrations of 14.4 and 15.5 mg/L in blood, and 73.7 and 82.4 mg/kg in liver [14]. Three subjects with blood concentrations of 9.0, 24.3 and 32.9 mg/L were determined as deaths attributed primarily to trazodone [15]. Non-toxic postmortem trazodone tissue (liver) concentrations have not been previously described.

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All specimens analyzed were collected at autopsy at the San Diego County Medical Examiner’s Office. Trazodone positive cases detected over an 8-month period (October 2013–June 2014) with sufficient and appropriate samples (peripheral blood, central blood and liver) were selected for this study. No cases showed obvious signs of decomposition or severe trauma; cases were not included if decomposition or severe trauma was noted by the medical examiner investigator, or observed during the autopsy. Autopsies were performed within 24–48 h after the reported time of death. Peripheral blood (20 mL) was drawn from the common iliac veins (blood returning from the leg and visually identified in the pelvis at autopsy) and stored in standard glass tubes containing sodium fluoride (100 mg) and potassium oxalate (20 mg). Central blood was collected from the heart or adjacent great vessels and placed in identical tubes. Sections of the upper right lobe of liver were collected and stored in a four-ounce container without preservative. All samples were stored at 4 8C until analyzed.

Similarly for liver analyses, 50 mL of trazodone stock solution was added to a 10 mL volumetric flask brought to volume with pork liver. Liver calibrators were made at levels of 0.20, 0.50, 1.0, 2.0, and 5.0 mg/kg. Liver specimens were homogenized by taking 5–6 g of liver specimen and blending it with an equal amount of deionized water to create a 0.5 g/mL (2) homogenate. Pork blood and liver have been routinely utilized in this laboratory for over 15 years. These specimens have been found to adequately represent human specimens with respect to extraction and drug recovery. Case specimens were extracted using appropriate dilutions to ensure that the quantitation was within the linear range of the calibration curve. Blood specimens were extracted using 0.5 mL of specimen; tissue specimens were prepared at a minimum 2 dilution. Specimens were extracted using 1-chlorobutane, following the addition of internal standard under slightly alkaline conditions. The organic solvent was removed and the resulting extract dried down. The residue was reconstituted with 85:15, 31 mM phosphate buffer:acetonitrile and injected onto a reversedphase phenyl column where separation, detection, and quantification were achieved using HPLC-photodiode array (DAD). Calibration curves were constructed from a minimum of four non-zero points and used a linear regression fit (r2  0.99). Calibrators were back calculated to original known concentrations and were within 20% of target value. A positive control sample was prepared (by an independent preparation of an independent stock solution) at a concentration of 0.75 mg/L (in whole-blood) for blood analyses. Similarly, positive control samples were prepared at a concentration of 2.0 mg/kg (in liver homogenate) for the liver analyses.

2.2. Drug screening

2.5. Instrumentation

Drug screening for all cases included, at least, blood alcohol and simple volatiles by GC-FID headspace analysis, 12 drugs of abuse panel by ELISA (cocaine metabolite, opiates, methamphetamine, benzodiazepines, cannabinoids, fentanyl, synthetic cannabinoids, oxycodone, methadone, zolpidem, carisoprodol, and buprenorphine) (Immunalysis Inc., CA), and an alkaline drug screen by gas chromatography–mass spectrometry (GC–MS) following solid phase extraction. Trazodone, when detected by the alkaline drug screen, was subsequently confirmed and quantified by reextraction and re-analysis using minor modification to a previously published calibrated, controlled and validated technique [16].

A 1200 series HPLC-DAD system (Agilent Technologies, Santa Clara, CA) with an automatic injector was used for analysis. A Nova-Pak Phenyl HPLC column (2.1 mm  150 mm, 4 mm particle size), and a matching column filter were used (Waters Corporation, Milford, MA). The method utilized was a minimally modified version of the method previously validated and published [16]. Analyses were performed using mobile phase containing phosphate buffer:acetonitrile (85:15) with a gradient elution with the concentration of acetonitrile increasing to 28% at 10 min and returning to 15% at 22 min. Thirty microliters of each extract was injected at a flow rate of 0.6 mL/min. Detection of eluent was monitored at 240 nm. Total run time was 30 min, with trazodone and clobazam eluting at about 11.0 and 16.0 min, respectively.

The study described herein examined 19 postmortem cases for liver, peripheral blood and central blood concentrations from known positive trazodone cases. These investigations present data of postmortem distribution, and provide further insight on how liver concentrations may correlate with those of blood, and assist with the interpretation of the drugs’ propensity for postmortem redistribution. 2. Experimental 2.1. Specimen collection and storage

2.3. Materials Trazodone was purchased from Grace Discovery Sciences (Deerfield, IL). The stock trazodone was dissolved in methanol at a concentration of 1.0 mg/mL. The internal standard used was clobazam and this was purchased from Cerilliant Corporation (Round Rock, TX). The stock clobazam was diluted in water to a concentration of 1.0 mg/L. HPLC grade acetonitrile (Omnisolv), HPLC grade methanol (Omnisolv) and Potassium Phosphate, Dibasic (BDH) were purchased through VWR (Radnor, PA). o-Phosphoric acid, 85% was purchased from Fisher Scientific (Fair Lawn, NJ). Deionized water was obtained from a Cascada AN water purification system manufactured by Pall (Ann Arbor, MI). A 31 mM phosphate buffer was formulated and pH adjusted to 3.5 with o-phosphoric acid. 2.4. Trazodone analysis A working intermediate standard was made by adding 25 mL of trazodone stock solution to a 10 mL volumetric flask. The solution was brought to volume with pork blood. Calibrators were made at levels of 0.05, 0.10, 0.50, 1.0, and 2.5 mg/L for blood analyses.

2.6. Validation An ultraviolet (200–350 nm) spectral match greater than 95% (matched to an established in-house library), a photodiode peak purity check, and a relative retention time confirmation were required for a positive compound identification. Appropriate matrix blank and negative control specimens were extracted with each batch of casework to confirm the lack of interference and/or contamination. No co-eluting compounds were observed. The limits of detection (LOD) were 0.02 mg/L for blood and 0.10 mg/kg for liver. Limits of quantification (LOQ), determined by the lowest calibration concentrations, were 0.05 mg/L for blood and 0.20 mg/ kg for liver. Accuracy of the method for the analyses of trazodone in whole-blood was established over 16 analyses (a 6-month timeframe) and was determined at 0.73 mg/L (or 97%) for the 0.75 mg/L positive control. The precision established for these data showed a coefficient of variation of 5.8%. Similarly, accuracy for the analyses of liver trazodone was established over five analyses and was 2.1 mg/kg (106%) for the 2.0 mg/kg liver homogenate control.

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Analysis of the precision of these data showed a coefficient of variation of 8.3%.

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the scene. Autopsy examination documented hepatomegaly, steatosis, and cirrhosis, hypertensive cardiovascular disease, and obesity.

3. Case reports 3.1. Cases of non-toxic or incidental use 3.1.1. Case 1 The decedent was a 56-year-old woman was found dead in bed at home. She had a history of diabetes mellitus and was non-compliant with her medications and diet. She also had a history of hypertension and sleep apnea. She had a c-pap machine but refused to use it. She was a tobacco smoker and had a history of illicit drugs abuse but there was no history of prescription medication abuse. Multiple prescription medications were found at the scene. Autopsy examination documented an obese woman with cardiovascular disease (cardiomegaly, right ventricular dilatation, and arteriolonephrosclerosis), marked congestion, edema of the lungs, and obesity. 3.1.2. Case 2 The decedent was a 62-year-old man with a history of ethanol and drug abuse, bipolar disorder, hepatitis C, and urolithiasis. He was incarcerated at a local jail and became uncooperative while being escorted back from a scheduled medical visit. After an altercation, he was cuffed and then released. He walked back to his cell within issues. The next morning he complained of intense pain and was later found unresponsive on his cell floor. Death was declared without medication intervention due to postmortem changes. Autopsy examination documented a gastrointestinal hemorrhage, evidence of hepatitis C with hepatic fibrosis, hypertensive cardiovascular disease, cholelithiasis, left nephrolithiasis, and minor blunt force injuries that did not contribute to death. 3.1.3. Case 3 The decedent was a 45-year-old man who was witnessed to ingest trazodone and oxycodone the night before his death. On the morning of his death he was witnessed to ‘‘seize,’’ collapse, and become unresponsive with apnea. He was transported to an area hospital where he was declared dead shortly after arrival. He had a history of sleep apnea and a remote Roux-en-Y gastric bypass. The autopsy documented cardiovascular disease (cardiomegaly, biventricular dilatation, mild billowing of the mitral valve), marked congestion and edema of the lungs, hepatomegaly with steatosis and fibrosis, and obesity. There was no significant trauma identified. 3.2. Drug related deaths where trazodone was not included in the cause of death, or as a contributing factor 3.2.1. Case 4 The decedent was a 56-year-old woman with a history of fibromyalgia with chronic pain, COPD, recent ankle sprain, ethanol and narcotic dependence, and tobacco smoking. She had a prescription for fentanyl patches which was renewed at a higher dose (75 mg/h) and had recently used one for pain. She was found by her spouse sitting on a floor of their home unresponsive. There was no history of suicidal ideation or attempts. Death was pronounced at the scene after a brief resuscitative effort. Autopsy examination documented mild hepatic steatosis, mild concentric left ventricular hypertrophy, mild arteriolonephrosclerosis, and emphysematous changes. There was no evidence of significant trauma. 3.2.2. Case 5 The decedent was a 47-year-old woman with a history of chronic alcohol abuse, hypertension, hyperlipidemia, hypothyroidism, and breast cancer. She was found unresponsive lying on the couch of her home by her spouse. She was pronounced dead at

3.2.3. Case 6 The decedent was a 54-year-old man with a history of atrial fibrillation and an unspecified back injury that he sustained at work several years prior to death. Medications found at the scene included carisoprodol, hydrocodone/acetaminophen, methocarbamol, oxycodone, quetiapine, sertraline, temazepam, tramadol, and trazodone. His mother found him unresponsive in bed. His death was confirmed at the scene. Autopsy examination documented bilateral acute bronchopneumonia, mild hepatic steatosis, fourchamber dilatation of the heart, and arteriolonephrosclerosis. 3.2.4. Case 7 The decedent was a 53-year-old woman with a history of arthritis, hypertension, GERD, hepatitis C and anxiety disorder. She was found unresponsive on her couch by a roommate and death was determined due to postmortem changes. She had been prescribed many medications for pain and was known to overmedicate. Autopsy examination documented nephrosclerosis, mild single vessel coronary artery atherosclerosis, mild interstitial fibrosis of the heart, congestion and edema of the lungs, and mild cerebral edema. 3.2.5. Case 8 The decedent was a 56-year-old woman with a medical history of bipolar disorder, asthma, pneumonia with sepsis, and polysubstance abuse. On the day of her death, she was awoken by her roommate and when she got up she fell and hit her head. She refused an ambulance and was helped back to bed. A few minutes later, the roommate noted the decedent to be in distress. She called 9-1-1. Shortly after paramedics arrived she went into cardiac arrest. She was transported to a local hospital emergency department where she died without successful resuscitation. She was hospitalized twice for polysubstance abuse approximately one year prior to her death. Autopsy examination documented blunt force head trauma, sternum and rib fractures consistent with CPR efforts, left lower lung lobe organized pneumonia, right pleural effusion, emphysematous changes, and mild hepatic steatosis. 3.2.6. Case 9 The decedent was a 53-year-old man appeared intoxicated the last time he was seen alive. Approximately one and half hours later, he was found unresponsive by security staff at the apartment complex where he resided. His death was pronounced at the scene. He had a medical history of heart disease, pancreatitis, and alcohol and tobacco use. Autopsy examination documented findings consistent with hypertensive and atherosclerotic cardiovascular disease, hepatic cirrhosis and steatosis, gastritis, pancreatitis with a pseudocyst, and pulmonary emphysema. There was no evidence of trauma contributing to death. 3.2.7. Case 10 The decedent was a 49-year-old woman with a history of chronic ethanol abuse, bipolar disorder, and depression. She was found unresponsive on her living room floor by her son. Death was confirmed at the scene due to postmortem changes. At the scene there were empty medication bottles, loose pills, and an empty 200-mL bottle labeled Vodka. The decedent’s sister reported that she suspected the decedent may have been overusing her prescription medications, as the decedent appeared to be occasionally overmedicated. Autopsy examination documented minimal hepatic steatosis, early aspiration pneumonia, mild

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arteriolonephrosclerosis, and a mildly fibrotic pancreatic parenchyma. 3.2.8. Case11 The decedent was a 42-year-old woman who was found unresponsive in her room by her boyfriend on the afternoon of her death. She was pronounced dead at the scene without resuscitation. She had a history of PTSD, chronic shoulder pain, and kidney stones. Multiple prescription medications were found at the scene. She had no recent complaints. Autopsy examination documented marked pulmonary edema and congestion, bilateral empyemas, acute bilateral streptococcus pyogenes pneumonia with evidence of septicemia, and centrilobular hepatic necrosis. 3.3. Drug related deaths where trazodone was included as a cause of death or a contributing factor 3.3.1. Case 12 The decedent was a 22-year-old man who was found on the morning of his death by his friends unresponsive after spending the night with friends on the front porch of an employer’s house. Friends attempted CPR and drove him to a local hospital emergency room. He was pulseless and apneic upon arrival and could not be resuscitated. He had a history of chronic ethanol abuse and depression, but no history of substance abuse. It was unknown if any drug paraphernalia were at the scene. Autopsy examination documented pulmonary congestion and edema, urinary retention, and hepatic steatosis. 3.3.2. Case 13 The decedent was a 32-year-old man who was a recovering heroin addict. He was reportedly clean for over a year. On the morning of his death, he was found on a bathroom floor by his spouse in their home. Drug paraphernalia including a metal spoon, a lighter, a capped syringe, and a small bag containing a dark substance were found at the scene near the body or in clothing on the body. No suicide note was found. Autopsy examination documented hepatic steatosis and cholelithiasis. 3.3.3. Case 14 The decedent was a 48-year-old man who was found by family unresponsive at home. The decedent had a history of alcoholism and schizophrenia. Autopsy examination documented a large, poorly masticated fragment of food obstructing the airway and hepatic steatosis. There was no evidence of trauma contributing to death. 3.3.4. Case 15 The decedent was a 62-year-old woman who was reportedly assaulted approximately 3 weeks prior to death. She sustained facial trauma as a result but there were no known sequelae. She had a history of chronic pain related to her lower back and a history of hypertension. She was found unresponsive at home by her son and was declared dead at the scene. Medications found at the scene included hydrocodone, trazodone, tramadol, and oxycodone. Autopsy examination documented acute bronchopneumonia, hypertensive and atherosclerotic cardiovascular disease, obesity, and osteoporosis. There was no evidence of trauma contributing to death. 3.3.5. Case 16 The decedent was a 44-year-old man found unresponsive on his bathroom floor after complaining of dizziness and slurred speech over several days prior to his death. Nineteen years prior, he sustained a traumatic brain injury after jumping out of a moving vehicle. He was in a coma for 6 months as a result. He returned to be able to perform normal activities of daily living. Since his

traumatic injury, he had a history of over self-medicating. Autopsy examination documented an obese male with urinary retention, acute bronchopneumonia, moderate single-vessel coronary artery atherosclerosis, encephalomalacia, and evidence of a right temporal lobe brain injury. 3.3.6. Case 17 The decedent was a 64-year-old woman with a history of back pain and a long history of pain medication abuse; the specific medications reportedly abused were not available. She went to a doctor’s appointment 3 days prior to her death and when she returned home, she seemed ‘‘out of it.’’ On the morning prior to her death, a friend witnessed her take a handful of pills. That afternoon the decedent was lethargic. On the morning of her death, a friend found her seated on a toilet, unresponsive. She was declared dead at the scene by medical attendants. Medications found in the residence were atorvastatin, baclofen, carisoprodol, lorazepam, ondansetron, and trazodone. Autopsy examination documented pulmonary edema and congestion, moderate coronary artery atherosclerosis, adrenal cortical hyperplasia, diverticulosis, and evidence of multiple abdominal operations. 3.3.7. Case 18 The decedent was a 55-year-old woman who was found unresponsive by her roommate at home. She had a history of chronic ethanol abuse and chronic pain. Prescription medications found at the scene included meloxicam, amitriptyline, sumatriptan, mirtazapine, cyclobenzaprine, famotidine, loratadine, and trazodone. Autopsy examination documented hepatomegaly with steatosis and early fibrosis, evidence of hypertensive cardiovascular disease, and mild pulmonary emphysema. There was minor blunt force trauma of the head, torso, and extremities but no evidence of significant trauma. 3.3.8. Case 19 The decedent was a 62-year-old woman with a history of hypertension, diabetes, anxiety, depression, pancreatitis, chronic back pain, and ethanol and prescription medication abuse. She was frequently reported to appear overmedicated and/or intoxicated and, at one point, presented to a local hospital for an accidental zolpidem overdose. She was found in bed unresponsive by her significant other with her face in a pillow. Prescription medications were found at the scene with numerous pills missing from a trazodone bottle that was inconsistent with the prescribed dosage recorded on the bottle – 36  100 mg pills missing in 19 days (prescription: 1  100 mg pill at bedtime). The autopsy documented mild to moderate cardiovascular disease with focal contraction band necrosis, arteriolonephrosclerosis, focal aortic valve calcifications, and steatosis with fibrosis of the liver. 4. Results and discussion A total of 19 cases were examined where blood [central (C) and peripheral (P)], and liver (L) were available for analysis. Trazodone concentrations and ratios for central to peripheral blood (C/P) and liver to peripheral blood (L/P) are shown in Table 1. Cause and manner of death (determined by board certified forensic pathologists) and the other drugs detected in each case are detailed in Table 2. Considering the ascribed causes of death – death resulting from causes other than medications/drugs (determined by board certified forensic pathologists) – together with previous reports of toxicity, the first three cases were deemed to represent examples of non-toxic or incidental use. Using these criteria, the non-toxic postmortem peripheral blood trazodone concentration ranged up to 0.97 mg/L (case 3 – a natural death) with a

I.M. McIntyre et al. / Forensic Science International 251 (2015) 195–201 Table 1 Peripheral blood, central blood and liver trazodone concentrations, and ratios. Case #

P (mg/L)

C (mg/L)

L (mg/kg)

C/P Ratio

L/P ratio (L/kg)

1 2 3 Mean Median S.D. Range

0.26 0.52 0.97 0.58 0.52 0.32 0.26–0.97

0.26 0.50 1.1 0.61 0.50 0.41 0.26–1.1

0.59 1.8 2.2 1.5 1.8 0.28 0.59–2.2

0.99 0.96 1.1 1.0 0.99 0.10 0.96–1.1

2.3 3.5 2.3 2.7 2.3 0.86 2.3–3.5

4 5 6 7 8 9 10 11 Mean Median S.D. Range

0.15 0.17 0.29 0.36 0.38 0.42 0.73 1.0 0.44 0.37 0.29 0.15–1.0

0.16 0.15 0.19 0.36 0.37 0.48 1.2 0.96 0.48 0.36 0.39 0.15–1.2

0.59 0.39 0.96 0.76 0.88 1.6 1.3 2.1 1.1 0.92 0.57 0.39–2.1

1.1 0.93 0.65 0.98 0.97 1.1 1.6 0.94 1.0 0.97 0.29 0.65–1.6

4.0 2.4 3.3 2.1 2.3 3.8 1.8 2.1 2.7 2.3 0.72 1.8–4.0

12 13 14 15 16 17 18 19 Mean Median S.D. Range

0.08 0.12 1.44 0.52 2.3 2.9 5.0 6.1 2.2 1.4 2.3 0.08–6.1

0.07 0.13 0.47 0.15 1.2 4.3 7.1 1.5 1.9 0.85 2.6 0.07–7.1

1.41 0.89 2.4 ND 4.1 23 26 3.8 8.7 3.8 11.3 ND-26

0.88 1.1 1.1 0.30 0.53 1.5 1.4 0.24 0.88 0.98 0.52 0.24–1.5

5.1 7.4 5.5 ND 1.8 8.0 5.2 0.63 4.8 5.2 3.0 ND-8.0

P = peripheral blood, C = central blood, L = liver, ND = not detected. Cases 1–3: natural deaths. Cases 4–11: Drug related deaths where trazodone was not included in the cause of death, or as a contributing factor. Cases 12–19: Drug related deaths where trazodone was included as a cause of death or a contributing factor.

corresponding liver concentration of 2.2 mg/kg. Overall, the nontoxic concentrations ranged from 0.26 to 0.97 mg/L (peripheral blood), 0.26 to 1.1 mg/L (central blood), and 0.59 to 2.2 mg/kg (liver). Eight cases (cases 4–11) were reported as drug related deaths (trazodone was not included in the cause, or as a contributing factor; determined by board certified forensic pathologists) – all were determined to be accidental drug deaths. The trazodone concentrations ranged from 0.15 to 1.0 mg/L (peripheral blood), 0.15 to 1.2 mg/L (central blood), and 0.39 to 2.1 mg/kg (liver). These concentrations were comparable to those of the three natural deaths. An additional eight cases (cases 12–19) were determined to be drug related deaths (determined by board certified forensic pathologists), including trazodone as a cause or contributing factor. Trazodone was not found to be the cause of death in its own right – it was always combined with other medications. Case 19, however, was positive only for ethanol 0.05% and diphenhydramine

Postmortem distribution of trazodone concentrations.

Non-toxic postmortem trazodone tissue (liver) concentrations have not been previously described. Liver trazodone concentrations were compared to perip...
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