The Source of Methadone in Overdose Deaths in Western Virginia in 2004

Abstract

Objectives

Methadone-related overdose deaths increased in the United States by 468% from 1999 to 2005. Current studies associate the nonmedical use of methadone with methadone-related deaths. This study describes medical examiner cases in rural Virginia in 2004 with methadone identified by toxicology and compares cases according to source of methadone.

Methods

In 2004, all intentional and unintentional poisoning deaths from the Office of The Chief Medical Examiner, Western District of Virginia, were reviewed to identify cases in which methadone was a direct or contributing cause of death. The Virginia Prescription Monitoring Program was reviewed for prescription opioids in the name of these identified decedents. Decedent participation in local opioid treatment programs (OTP) was also assessed.

Results

The source of methadone in the 61 methadone-related overdose deaths was mostly nonprescribed (67%), although 28% of decedents were prescribed methadone for analgesia. Only 5% of decedents were actively enrolled in an OTP. The majority of deaths were attributed to polysubstance overdose.

Conclusions

The majority of methadone overdose deaths in this study were related to illicit methadone use, rather than prescribed or OTP uses. Interventions to decrease methadone-related deaths should focus on reduction of nonprescription use of methadone.

Methadone exhibits a long and variable half-life of 15 to 55 hours together with the potential for multiple drug interactions (Wolff, 2002). Pharmacokinetic studies of methadone indicate that it has high oral bioavailability, a rapid and extensive distribution phase into the tissues of the brain, liver, kidneys, muscle, and lungs, and a very slow elimination phase as these extravascular sites slowly release methadone into the plasma (Intrussi and Verebely, 1972; Inturrisi et al., 1987). The elimination half-life of methadone has considerable interindividual variability due to genetic differences and environmental factors (Eap et al., 2002). In addition, sustained respiratory depression lasting 24 to 48 hours occurs despite the analgesic effect of methadone lasting only 4 to 6 hours (Wolff, 2002). Effects are intensified in methadone-naive patients, patients nonadherent to dosing regimens, those using multiple substances to attain euphoria, and patients prescribed CYP450-inducing medications. Liver dysfunction further prolongs elimination of methadone. These aforementioned characteristics increase methadone's potential for delayed toxicity and poisoning relative to other opioids (Wolff, 2002).

Methadone has been used for the outpatient treatment of opioid addiction since 1966 (Joseph et al., 2000). Methadone maintenance treatment decreases illicit opioid use and decreases mortality among opioid-dependent patients (Gronbladh et al., 1990; Caplehorn et al., 1996; National Institutes of Health, 1999). Outside opioid treatment programs (OTPs), methadone prescribing surged in the last decade because of its reasonable cost and efficacious analgesic profile (Wheeler, 2000; Dickerson, 2001; Oregon Department of Human Services, 2003; Substance Abuse and Mental Health Services Administration [SAMHSA], 2004). Methadone prescriptions increased by 5-fold in New Hampshire from 2000 to 2003 (Andrew, Duval, abstract presented at the Joint Meeting of SOFT and TIAFT), 5-fold in Oregon from 1997 to 2001 (Oregon Department of Human Services, 2003), and 4-fold in North Carolina from 1997 to 2001 (Ballesteros et al., 2003; US Department of Justice [USDOJ], 2004). Similar pattern increases were noted for oxycodone and hydrocodone prescriptions, though to a lesser degree (USDOJ, 2004). From 1999 to 2005 methadone poisoning increased by 468% nationwide, while poisoning deaths due to heroin increased by 2.4% and other synthetic opioids increased by 138% (Fingerhut, 2008).

Given the concomitant rise in methadone prescribing and methadone-related deaths, some have hypothesized that physician inexperience prescribing methadone for chronic pain is a potential contributor, and have taken steps to better educate physicians about appropriate prescribing practices (Oregon Department of Human Services, 2009; SAMHSA, 2009). In 2006, the Food and Drug Administration also lowered the starting dosage recommendation of methadone to 2.5 to 10 mg every 8 to 12 hours from 2.5 to 10 mg every 3 to 4 hours as needed for initiation of analgesic therapy in opioid-naive patients (Roxane Laboratories, 2000, 2006). The new recommended initial dose for treatment of opioid dependence is no more than 40 mg/d (Roxane Laboratories, 2006). Alternative reasons for the concomitant rise in methadone prescribing and mortality include increased opportunities for the nonmedical use and diversion of methadone (Cairns et al., 1996; Lehder et al., 2002; Sorg and Greenwald, 2002; Ballesteros et al., 2003; USDOJ, 2004; Paulozzi et al., 2009). Empiric data regarding the source of methadone in overdose deaths are limited. Estimates of the contribution of physician methadone prescriptions to opioid overdose deaths vary widely from 15% to 75% of medical examiner cases (Barrett et al., 1996; Ballesteros et al., 2003; Gagajewski and Apple, 2003; Shah et al., 2005; Paulozzi et al., 2009). Only 2 studies, under the same Centers for Disease Control and Prevention investigation, have used a prescription-monitoring program to link methadone prescriptions to overdose deaths (Hall et al., 2008; Paulozzi et al., 2009). Both studies found evidence of significant prescription opioid nonmedical use and a high prevalence of a history of substance abuse among overdose decedents in West Virginia, regardless of whether they were prescribed methadone from a physician or not (Hall et al., 2008; McLellan and Turner, 2008; Paulozzi et al., 2009).

During the last decade there has been a 300% increase in medical examiner--investigated deaths in western Virginia identifying prescription opioids as a direct or contributing cause of overdose death (Wunsch et al., 2009). A recent study of opioid-related deaths in western Virginia from 1997 through 2003 reported that methadone was the most commonly identified opioid associated with accidental overdose (Wunsch et al., 2009). In that study, the source was not determined primarily because the Prescription Monitoring Program (PMP) was not established in Virginia until 2003.

The objective of this study was (a) to describe methadone-related deaths secondary to poisoning in western Virginia from January 1, 2004, to December 31, 2004, and (b) to determine the source of the medication by linking medical examiner and OTP records with Virginia's PMP. We hypothesized that in most cases the source of methadone was from physician prescriptions for analgesia rather than for opioid addiction treatment or an illicit source.

Methods

Study Design and Setting

This is a retrospective descriptive case series of persons who died from methadone poisoning in western Virginia from January 1, 2004, to December 31, 2004. Poisoning in this study is defined as death associated with intoxication by licit and/or illicit drug substances as determined by the Office of The Chief Medical Examiner (OCME), Western District, Va, and will be referred to by the term “overdose.”

Cases were drawn from the OCME, Western District, Va. The office's jurisdiction services 34 counties with a population of 1.6 million people. The region is predominantly rural with 7 metropolitan statistical areas, each with fewer than 100,000 people. Three private OTPs serve this region with a combined 2004 census of 1505 patients. All OTPs in the region participated in the study.

The institutional review board at the Virginia College of Osteopathic Medicine approved this study. Authorization to review medical examiner files and prescription monitoring data was obtained from the OCME who had access to the Virginia PMP for OCME cases.

Case Identification

Medical examiner cases include suspicious, violent, or unnatural deaths, or deaths related to the public interest such as incarcerated prisoners or patients in mental institutions. In the Western District, the suspicion of licit or illicit drug poisoning in a death confers jurisdiction to the OCME. Therefore, referrals of all suspected poisoning deaths in the region are made to the OCME for further evaluation. The cause of death in cases when a decedent has been hospitalized for greater than 24 hours is determined by the attending hospital physician and therefore is exempt from OCME referral. Cases when a decedent dies within 24 hours of hospitalization are referred to the OCME for cause of death determination. All decedents referred to the OCME undergo toxicology testing to screen for illicit drugs, ethanol, and prescribed pharmaceuticals including opioids, stimulants, depressants, and other prescribed medications (eg, antidepressants and antiemetics). All methadone deaths reviewed for this study were subject to a complete autopsy with comprehensive toxicological analysis including quantitative determinations of drug and drug metabolite concentrations.

Determination of cause and manner of death is the statutory responsibility of the medical examiner. The causes of death in this analysis were determined by medical examiners on the basis of the information gathered from the toxicological data (including postmortem methadone blood concentrations), autopsy findings, police reports, scene photographs, accident reconstruction, and witness statements.

For this analysis, all Western District medical examiner cases occurring between January 1, 2004, and December 31, 2004, where the cause of death was poisoning, were identified for possible inclusion in the study. Poisoning deaths where illicit drugs or medications were present on toxicological analysis and were a direct or contributing cause of death were selected for further review. Methadone-related cases were defined as those deaths where the manner of death was intentional and unintentional, methadone was present in the toxicological analyses, and methadone was deemed a direct or contributing cause of death by the medical examiner. ▒Each decedent was given a unique identifier for tracking purposes.

Data Sources

We collected data from 3 sources: (1) medical examiner records, (2) OTP medical records, and (3) Virginia PMP database records.

Medical examiner records included autopsy reports; toxicological reports; hospital records including information about previous overdoses or suicide attempts; physician notes and records including information about a history of substance abuse, pain syndromes, history of mental illness, and medication records; death investigation and death scene reports including photographs and documentation of medications or drug paraphernalia found at the death scene; police reports including witness statements and information regarding previous criminal histories; and death certificates that include demographic information including the date of birth, sex, race, and home address. These records were extensively reviewed and pertinent data extracted for each decedent case.

Executive directors of the 3 regional OTPs were presented a list of decedents including name and date of birth and asked to verify decedents who were patients in their clinic at any time in the past. After confirming OTP enrollment, the principal investigator (MBW) extracted information from the patients' OTP medical charts including admission and discharge information, dosing orders, take-home allowance, and urine drug screen result history. A decedent could also be classified as OTP source if there was compelling evidence in the medical examiner files for active methadone maintenance therapy at an OTP other than the 3 that were contacted.

The Virginia PMP is an online database maintained by the Department of Health Professions and requires pharmacies, nonresident pharmacies, permitted physicians, and physicians holding permits to sell controlled substances to report dispensation of schedule II-, III-, and IV-controlled substances. The PMP was initiated in August 2003 as a pilot program in the region of western Virginia served by the Western District OCME. During the pilot program, only schedule II-controlled substances were tracked by the PMP. Methadone prescribed by an OTP is not listed in the PMP. Using each decedent's name and date of birth, the PMP was queried for any dispensed schedule II-controlled substances from August 2003 to date of decedent death, but no later than December 31, 2004. Reports generated from the PMP database included name of medication, the time when date prescription was filled, medication dose, quantity of medication dispensed, prescribing physician, and pharmacy name and address.

Decedent Characteristics

Decedent sociodemographic characteristics were abstracted from medical examiner files and included age at death (years), sex (male, female), and race (white, other). Decedent's place of residence was classified as rural or nonrural (eg, metropolitan or micropolitan) according to the Government Office of Management and Budget definitions (Federal Register, 2000). Decedents' history of substance abuse was defined as any autopsy evidence of nonmedical route of drug administration, documentation in OCME and medical records of a history of addiction or substance abuse, history of unintentional drug overdose requiring hospitalization, history of treatment in a substance abuse treatment program, or a positive toxicology screen for cocaine, marijuana, or heroin on postmortem toxicological examination. Decedents were classified as having questionable prescription activity if there was PMP evidence of greater than or equal to 4 physicians prescribing them opioids at one time or greater than or equal to 4 pharmacies used at one time (Katz et al., 2010).

Medical records within the medical examiner file were also searched for evidence of previous methadone overdose history, suicide attempt, or previous or current incarceration. Decedents were classified as having had a previous methadone overdose history or a previous suicide attempt if there was documentation within either a hospital record or other medical record. Decedents were classified as having a previous or current history of incarceration as documented in their police investigations.

The primary cause of death (ie, methadone only vs polysubstance overdose) and manner of death were extracted from OCME autopsy report diagnoses as found in the medical examiner file.

Source of Methadone

For each decedent, we attempted to identify all possible sources of methadone. The possible sources of methadone were (a) prescribed by a non-OTP physician, (b) prescribed by an OTP-physician, or (c) illicit. Decedents were classified as having received a prescription from a non-OTP physician (a) when their name and a corresponding methadone prescription were found in the PMP or (b) when a current prescription for methadone in the decedent's name was found at the death scene. Decedents were classified as having received methadone from an OTP if they were enrolled in an OTP within the 2 weeks before death. Decedents were classified as obtaining methadone from an illicit source when the decedent did not have a prescription for methadone in the PMP, from an OTP, or at the death scene. Cases in which there was suspicion for drug sharing or stealing were also classified as illicit source.

Toxicological Analyses

Postmortem blood concentrations of methadone were used along with all available objective information in the cases to formulate a cause of death statement. Postmortem toxicology data were available for all decedents in this study and included mean methadone, other drugs, and drug metabolites concentrations. The mean methadone concentrations reported were blood or body fluid measurements representing both central and peripheral collection sites, although, whenever available, quantitative analyses of methadone were performed in a peripheral specimen of blood collected at autopsy (eg, femoral or iliac blood). Quantitative analyses of drugs and drug metabolites in postmortem blood, body fluids (urine, gastric fluid, and bile), and tissues (liver) were performed by a number of validated analytical methods employing gas chromatography-mass spectrometry, gas chromatography-mass spectrometry/selected ion monitoring, high-performance liquid chromatography with diode array or fluorescence detection, and gas chromatography with electron capture detection.

Statistical Analyses

Descriptive statistics were utilized to report decedent characteristics and assess overall associations between decedent characteristics and source of methadone. Chi-square tests were employed for categorical data and simple regression with Wald test for continuous variables. Bivariate associations between decedent characteristics and source of methadone were identified using simple logistic regression.

Results

Decedent Characteristics

In 2004, there were 203 overdose cases examined by the OCME. Methadone was detected by toxicology and deemed a direct or contributing cause of death in 68 of those cases (34%). Seven cases were excluded because decedents resided outside of the Virginia PMP pilot study area. Table 1 describes the characteristics of the remaining 61 decedents who exhibited an average age of 36 years (age range, 19-59 years), were predominantly white men, and were nearly as likely to be from rural areas as nonrural areas. Forty-six percent did not meet study criteria for history of substance abuse, yet autopsy and final toxicological analysis reported the cause of death in the majority of cases (61%) to be polysubstance overdose. The average number of substances contributing to decedents' deaths was 3, with a range of 1 to 6 substances. Of note, 6-acetylmorphine, the analytical toxicological marker for heroin, was identified in only 1 of the 61 decedents (#55; Table 2).

TABLE 1. Methadone-Overdose Decedent Characteristics, Western Virginia 2004.

Characteristic	Overall (N = 61)	Source of Methadone
		Illicit (n = 41)	OTP (n = 3)	Prescription (n = 17)	P*
		Mean age, years (SE)	36 (1.3)	33 (1.6)	25 (0.9)	44 (1.6)	<0.001
Sex
Female	22 (36%)	14 (34%)	1 (33%)	7 (41%)	0.875
Race
White	58 (95%)	38 (93%)	3 (100%)	17 (100%)	0.463
Residence
Rural	27 (44%)	19 (46%)	2 (67%)	6 (35%)	0.539
History of substance abuse	33 (54%)	23 (56%)	3 (100%)	7 (41%)	0.153
Cause of Death
Polysubstance overdose†	37 (61%)	24 (58%)	1 (33%)	12 (71%)	0.424
Concomitant drugs on toxicology
Any	47 (77%)	31 (76%)	2 (67%)	14 (82%)	0.778
Antidepressants‡	14 (23%)	5 (12%)	0 (0%)	9 (53%)	0.002
Benzodiazepines§	22 (36%)	18 (44%)	1 (33%)	3 (18%)	0.165
Other prescribed opiates‖	18 (30%)	15 (37%)	0 (0%)	3 (18%)	0.183
Ethanol	11 (18%)	7 (17%)	1 (33%)	3 (18%)	0.778
Cocaine¶	8 (13%)	4 (10%)	0 (0%)	4 (24%)	0.290

^*Wald χ² test obtained from simple linear regression.

^†Drug classes detected include antidepressants, benzodiazepines, opioids, alcohol, and cocaine.

^‡Antidepressants include mirtazapine, sertraline, clomipramine, citalopram, amitriptyline, and venlafaxine.

^§Benzodiazepine parent drug and metabolites include diazepam, nordiazepam, clonazepam, alprazolam, and desoxychlordiazepam.

^‖Other opiates include hydrocodone, oxycodone, morphine, and hydromorphone.

^¶Cocaine or cocaine metabolites.

OTP, Opiate Treatment Program; SE, standard error.

TABLE 2. Individual description of methadone-overdose decedents, western Virginia 2004.

A. Decedents who illicitly obtained methadone
#	Cause of Death	Known Co-morbidities	Postmortem Toxicology‡	Identified Non-prescribed medications at death scene	Prescribed medications at death scene	Additional Relevant Medical Examiner Record Information
1	Drug overdose	Asthma	Methadone (0.27mg/L) Oxycodone	Oxycontin® 40mg Benadryl	Albuterol inhaler	-Released from prison within 30 days of death.
3	Arteriosclerotic Heart Disease and Combined Opiate drug use	Heart disease Hypertension Tobacco abuse High Cholesterol Depression	Dihyrdocodeine Hydrocodone Methadone (0.18mg/L) Mirtazapine Morphine Normeperidine	None	Morphine Sulfate Carvediolol Simvastatin Oxycodone/Acetaminophen Clopidogrel Aspirin Pantoprazole Lisinopril Coumadin	-Motor vehicle accident (MVA) five days before death.
4*	Drug Toxicity	Hx of opiate abuse Depression	Methadone (0.41mg/L) Sertraline	None	Sertraline	None.
						* Opiate Treatment Program (OTP) Details: -Discharged from OTP: 4 months prior to death -Total number of OTP enrollments: 1 -Length of OTP enrollment: 22 months -Methadone dose at discharge: 5mg -Highest methadone dose: 115mg/day -Methadone “take homes”: 6 per week
5	Methadone Poisoning	Back pain Hx of polysubstance abuse	Citalopram Diazepam Methadone (0.44mg/L) Nordiazepam	Methadone liquid	None	-Reported to frequent the emergency department for pain complaints. -History of use of cannabis and amphetamines during pregnancy. -Attended a party the night of death.
7	Mixed Drug overdose	Depression Hx of substance abuse	Chlorpheniramine Codeine Methadone (0.52mg/L)	None	Diazepam Paroxetine Verapamil Promethazine	-Family member is prescribed methadone.
9*	Combined Opiate and Anxiolytic Overdose	Hx of IV Drug Abuse	Alprazolam Ethanol Hydrocodone Methadone (0.55mg/L)	None	Alprazolam	-White power residue in plastic straw found at death scene
						* OTP Details: -Discharged from OTP: 1.5 months prior to death -Total number of OTP enrollments: 3 -Length of OTP enrollments: first unknown; second 21 months; third 7 months -Methadone dose at discharge: first unknown; second 110mg/day; third 70mg/day -Highest methadone dose: 110mg/day -Methadone “take homes”: first unknown; second 6 per week; third 5 per week
11	Pneumonia due to methadone poisoning	Seizure disorder Hx of intimate partner violence	Methadone (0.49mg/L) Phenytoin	None	Phenytoin	None
12	Mixed Drug Toxicity	None	Diazepam Hydrocodone Methadone (0.35mg/L) Nordiazepam Oxycodone	Hydrocodone/Acetaminophen Methadone	None	None
14*	Methadone Toxicity	Hx of Opiate Abuse	Alprazolam Diazepam Methadone (0.55mg/L) Nordiazepam	Methadone 10 mg Marijuana	None	None
						* OTP Details: -Discharged from OTP: 2 months prior to death -Total number of OTP enrollments: 1 -Length of OTP enrollment: 11 months -Methadone dose at discharge: 25mg/day -Highest methadone dose: unknown -Methadone “take homes”: none
16°	Methadone overdose	Depression Hx of polysubstance abuse Hx of suicide attempts	Methadone (0.23mg/L) Diazepam		Etodolac Trazodone Methocarbamol Hydroxyzine pamoate Methadone Busiprone	-Primary care provider is out of state at a Veterans Affairs
19	Methadone Toxicity	None	Methadone (0.36mg/L)	Methadone Alprazolam	None	None
20	Mixed drug toxicity	None	Diazepam Methadone (0.24mg/L) Nordiazepam	Methadone Alprazolam	None	None
21	Drug Toxicity	None	Methadone (0.27mg/L)	6 Empty Methadone vials (prescribed for family member)	None	-Homeless -Family member was enrolled in an OTP
22	Mixed Drug Toxicity	None	Alprazolam Ethanol Methadone (0.47mg/L)	Hydrocodone Temazepam	None	None
25*	Mixed Drug Toxicity	Hx of opiate abuse ADHD	Diazepam Ethanol Hydrocodone Methadone (0.49mg/L) Nordiazepam	Oxycodone Methadone 10 mg Diazepam Atomoxetine	None	-Reportedly sells drugs. -Received 90 tabs of methadone from a physician while enrolled in OTP.
						* OTP Details: -Discharged from OTP: 2.5 months prior to death -Total number of OTP enrollments: 2 -Length of OTP enrollment(s): first 11 months; second 19 days -Methadone dose at discharge: 60mg/day -Highest methadone dose: unknown -Methadone “take homes”: none
26	Drug Toxicity	None	Benzoylecgonineˆ Hydrocodone Methadone (0.53mg/L)	None	Diazepam	-Mirror and straw found at death scene
27*	Opioid drug poisoning**	Hx of polysubstance abuse and IV drug use Depression Hx of suicide attempts	Alprazolam Methadone (2.10mg/L)	None	None	-Hx of several DUI arrests. -Used syringe found at scene.
						* OTP Details: -Discharged from OTP: 8 months prior to death -Total number of OTP enrollments: 2 -Length of OTP enrollments: first 17 months; second 8 months -Methadone dose at discharge: 95mg/day -Highest methadone dose: unknown -Methadone “take homes”: none
29	Methadone Toxicity	Hx of IV drug use Hepatitis C	Methadone (0.26mg/L)	None	None	-Reportedly given or stolen methadone from a work colleague.
30	Drug Toxicity	Hx of opiate abuse Hx of alcohol abuse	Methadone (0.50mg/L)	Alprazolam	Hydrocodone	-Decedent was reportedly drinking heavily the night before death.
31	Opioid Drug Poisoning due to usage of methadone	Depression	Methadone (0.27mg/L)	None	Oxycodone/Acetaminophen Amitriptyline Hydrocodone	-Decedent reportedly purchased methadone from an acquaintance and took it prior to death.
32	Drug Toxicity	Hx of substance abuse Back pain	Diazepam Methadone (0.64mg/L) Nordiazepam	Marijuana	None	-Recently started diazepam for back pain.
35	Mixed Drug Toxicity	Hx of substance abuse	Benzoylecgonine Cocaine Diphenhydramine Methadone (0.29mg/L)	None	None	None
36	Drug Toxicity	Schizophrenia Hx of IV drug use	Alprazolam Methadone (0.60mg/L)	Methadone Liquid methadone (prescribed for family member) Alprazolam	Amitriptyline Quetiapine Propanolol	-Family member was enrolled in an OTP
38	Mixed Drug Toxicity	Hx of substance abuse	Hydrocodone Methadone (0.30mg/L)	None	None	None
40	Drug Toxicity	Chronic pain	Alprazolam Citalopram Methadone (0.16mg/L) Promethazine	Marijuana Pioglitazone Amlodipine	Naproxen Trazodone Escitalopram	-Decedent was receiving disability.
41	Mixed Drug Toxicity	Anxiety Depression Chronic pain	Clonazepam Ethanol Fentanyl Hydrocodone Methadone (0.48mg/L)	Clonazepam Hydrocodone/Acetaminophen Bupropion	Clonazepam (27 short◆) Hydrocodone Oxycodone/Acetaminophen (24 short) Olanzepine Paroxetine	-Needles found at the death scene
42	Mixed Drug Toxicity	Recent pregnancy Hx of polysubstance abuse	Benzoylecgonine Methadone (0.24mg/L) Oxycodone	None	None	-Post partum within 30 days at time of death. -Evidence of intravenous drug use found on autopsy.
45	Drug Toxicity	Depression	Methadone (0.59mg/L)	None	Sertraline	None
46	Edema of the lungs due to Opioids	Hx of drug abuse Migraines	Diphenhydramine Methadone (0.55mg/L) Norpropoxyphene	None	Zolpidem Clonazepam Methocarbamol Lorazepam Oxycodone/Acetaminophen	-Decedent was employed as a medical provider at an OTP.
47	Mixed Drug Toxicity	Hx of cocaine abuse	Chlorpheniramine Diazepam Hydrocodone Methadone (0.98mg/L) Nordiazepam	Alprazolam	None	-Decedent reportedly bought methadone from a stranger.
48	Methadone Poisoning	Hx of substance abuse	Methadone (0.62mg/L)	None	None	None
49	Combined Opioid Drug and Alcohol	None	Ethanol Methadone (0.31mg/L)	None	None	-Family member prescribed methadone for pain. -Family member reportedly shared 30mg of methadone with decedent.
52	Opioid Drug Poisoning due to usage of methadone	None	Diazepam Diphenhydramine Methadone (0.24mg/L) Nordiazepam	Hydrocodone	None	-Family member prescribed hydrocodone.
53	Pneumonia due to methadone poisoning	None	Methadone (1.8mg/L)	None	None	-Hx of multiple incarcerations
55	Accidental Heroin toxicity	Hx of substance abuse Hepatitis C	6-Acetylmorphine Codeine Methadone (0.05mg/L) Morphine	None	None	None
58	Methadone Toxicity	Anxiety Depression Pain	Diazepam Methadone (0.46mg/L) Nordiazepam Trazodone Venlafaxine	None	Diazepam (23 pills short) Trazodone Venlafaxine Celecoxib	None
59	Opioid Poisoning due to usage of methadone	Hx of substance abuse Depression Hx of suicide attempt	Diazepam Methadone (1.0mg/L) Nordiazepam	None	None	-Was known to associate with an illicit methadone user.
62	Mixed Drug Toxicity	None	Ethanol Methadone (0.21mg/L)	None	None	-Known to have had excessive alcohol the night before death -A family member had a known substance abuse problem
64	Mixed Drug Toxicity	Anxiety Bipolar disease Hx of alcohol abuse	Ethanol Hydrocodone Methadone (0.54mg/L)	None	Lorazepam Divalproex Paroxetine Propanolol	-Known to drink 12-18 beers/day
65	Opioid poisoning due to usage of methadone	Cirrhosis Pain Anxiety	Methadone (0.20mg/L)	None	Tramadol Diazepam	None
68	Mixed Drug Toxicity	Depression	Benzoylecgonine Cocaine Diazepam Fentanyl Methadone (unknown) Nordiazepam	None	Doxepin	-Family members are prescribed methadone and other opiate medications for analgesia.

B. Decedents who obtained methadone from an opiate treatment program
#	Cause of Death	Co-morbid condition	Postmortem Toxicology‡	Identified Non-prescribed medications at death scene	Prescribed medications at death scene	Opiate treatment program details	Additional Relevant Medical Examiner Record Information
2	Drug Toxicity	Hx of substance abuse	Methadone (0.49mg/L)	Diphenhydramine Eletriptan Acetaminophen Promethazine Meclizine Sibutramine Spironolactone Hydrochlorothiazide Clonazepam Phendimetrazine	Methadone liquid (zero remaining) (prescription written 6 months before death)	-Total number of OTP enrollments: 2 -Length of OTP enrollments: first unknown length; second 4 days -Methadone dose at discharge: 30mg/day -Highest methadone dose: unknown -Methadone “take homes”: none Death same day as last methadone dose	-Decedent had a UDS with THC in his urine during 2003 OTP enrollment.
17	Methadone Toxicity	Hx of substance abuse Depression Anxiety	Diazepam Methadone (1.20mg/L) Nordiazepam	None	Methadone Topiramate Escitalopram Quetiapine Clonazepam	-Total number of OTP enrollments: 1 -Length of OTP enrollments: 24 months, 3 days -Methadone dose at discharge: 105mg/day -Highest methadone dose: unknown -Methadone “take homes”: two Death same day as last methadone dose	- Decedent was given take home methadone six days before death.
18	Mixed Drug Toxicity	Hx of opiate abuse	Ethanol Methadone (0.62mg/L)	None	None	-Total number of OTP enrollments: 2 -Length of OTP enrollments: first 2.5 months; second 17 months -Methadone dose at discharge: unknown -Highest methadone dose: 85mg/day -Methadone “take homes”: none Death two days after last methadone dose	None

C. Decedents who were prescribed methadone by a non-OTP physician (PMP group)
#	Cause of Death	Known Co-morbidities	Postmortem Toxicology‡	Identified Non-prescribed medications at death scene	Dose of methadone	Number of Opiate Prescribers	Rx to deathª	Additional Relevant Medical Examiner Record Information
				Prescribed medications at death scene		Number of Pharmacies
6**	Methadone Poisoning	Hx of alcoholism Depression Chronic pain Hx Suicide attempts	Desoxychlor-diazapam Diphenhydramine Methadone (0.73mg/L) Nordiazepam Trazodone	None	40mg every 6 hrs	Unknown	3 days	-Methadone prescription at scene from Veteran's Affairs facility -Known to drink a case beer/day
				Methadone (52 short◆) Oxycodone/Acetaminophen		Unknown
8	Combined Drug Overdose	Chronic pain Depression	Methadone (0.36mg/L) Sertraline	None	20mg daily and 20mg TID	Two	5 days	-Used syringes found in shaving kit.
				Methadone 10mg (72 short) Zolpidem Alprazolam Sertraline		One
13**	Mixed Drug Toxicity	Chronic knee pain	Hydrocodone Methadone (0.27mg/L)	None	Unknown	Unknown	Unknown	-On house arrest at time of death.
				Hydrocodone Methadone Aspirin Alprazolam Atenolol Hydrochlorothiazide		Unknown
23	Mixed drug toxicity	Chronic neck pain Bipolar disorder	Carbamazepine Clomipramine Lamotrigine Methadone (0.17mg/L)	Tramadol Methadone (41 short) Alprazolam	10mg Q 12 hrs	One	7 days	None
				None		One
24	Mixed drug toxicity	Chronic back pain Cirrhosis Heart disease	Amitriptyline Citalopram Methadone (0.36mg/L)	Clonazepam Methadone Citalopram	Unknown	Two	4 days	None
				None		Two
28	Drug toxicity	Chronic back pain Depression Scoliosis Hx of suicide attempts	Amitriptyline Citralopram Cyclobenzaprine Methadone (0.51mg/L) Norpropoxyphene Nortriptyline Propoxyphene	None	30mg Q 8 hrs	Two	2 days	-Pt dismissed from one practice several days prior to death due to positive urine drug screen for benzodiazepines. Pt went to a different physician two days before death and received prescription for methadone.
				Clonazepam Methadone		One
33	Mixed drug toxicity	Chronic arthritis	Benzoylecgonine Citalopram Cyclobenzaprine Hydrocodone Methadone (0.33mg/L) Trazodone	Methadone (24 short) Hydrocodone/Acetaminophen	10mg TID	Three	6 days	None
				None		Two
34	Mixed Drug Toxicity	Anxiety Klippel-Trenaunay Syndrome Chronic pain Hx of cocaine abuse Depression Hx suicide attempt	Citalopram Methadone (0.28mg/L) Promethazine Quinine Trazodone	None	10mg Q 4 hrs	Three	27 days	-Hospitalized five days prior to death. -Received methadone and alprazolam at hospital admission.
				Alprazolam Methadone 10mg Quinine Escitalopram		Two
37	Combined Drug Poisoning	Depression Chronic Pain Anxiety	Benzoylecgonine Ethanol Methadone (0.14mg/L) Promethazine Trazodone Venlafaxine	None	30mg BID	One	2 days	None
				Trazodone Venlafaxine Methadone 10mg (2 short) Alprazolam Cyclobenzaprine Hydroxypam Risperidone		One
39	Combined Drug Poisoning	Depression Chronic Pain Hx of substance abuse	Alprazolam Ethanol Methadone (0.12mg/L) Mirtazepine Promethazine	Methadone	Unknown	Three	5 days	None
				Methadone Clonazepam Paroxetine Mirtazepine		Six
43	Mixed Drug Toxicity	Chronic Pain Degenerative Joint Disease Anxiety	Diazepam Methadone (0.50mg/L) Nordiazepam Promethazine	Methadone 10mg Diazepam 10mg	Unknown	Two	24 days	None
				Methadone Hydrocodone/Acetaminophen Diazepam		Two
50	Methadone Poisoning	Chronic Back Pain Hx of opiate abuse Depression	Methadone (0.69mg/L)	None	5mg Q 6 hrs	One	4 days	-Decedent reportedly took more methadone than prescribed the night of death.
				Methadone (86 short) Alprazolam (18 short) Sertraline Neurontin Valdecoxib		One
51	Methadone Poisoning	Chronic back pain Hx of opiate abuse	Methadone (0.74mg/L) Diphenhydramine	None	Unknown	Two	3 days	None
				None		Two
56	Mixed Drug Toxicity	Hx of substance abuse	Benzoylecgonine Methadone (0.71mg/L)	Methadone liquid Neurontin	10mg BID	Two	4 days	None
				Methadone 10mg		Three
63	Mixed Drug Toxicity	Manic depression	Ethanol Methadone (0.28mg/L) Sertraline	None Sertraline Alprazolam	Unknown	One One	3 days	None
66	Drug Toxicity	None	Methadone (0.59mg/L)	None	Unknown	Two	One year	None
				None		Two
67	Pneumonia due to combined opiate and stimulus overdose	Chronic Neck and Hip Pain Hx of methadone overdose	Benzoylecgonine Cocaine Methadone (0.90mg/L)	None	Unknown	Two	6 days	-Hospitalized seven days prior to death for non-fatal methadone poisoning.
				Hydromorphone		Five

^‡Postmortem blood methadone concentration (mg/L) in parentheses

^*History of methadone maintenance therapy (MMT) in the last one year, but not in the last two weeks.

^°Prescribed medications had several physicians names.

^ˆBenzoylecgonine is a metabolite of cocaine.

^◆Number short equals the total number of pills missing from the pill bottle at the death scene. This number is determined by date of prescription, prescription instructions, and date of death.

^**Suicide.

^‡Postmortem blood methadone concentration (mg/L) in parentheses.

^‡Postmortem blood methadone concentration (mg/L) in parentheses.

^**Methadone prescription bottle in the decedents' name found at the death scene, but not in the Prescription Monitoring Program Database.

^ªThis is the time between prescription being filled at the pharmacy and decedent's death.

^◆Number short equals the total number of pills missing from the pill bottle at the death scene. This number is determined by date of prescription, prescription instructions, and date of death.

Table 2 provides a full qualitative report about each decedent. Among cases with a history of incarceration (n = 3), 1 decedent (#13) was on house arrest at the time of death and 1 decedent (#1) was released from jail within 30 days of death. One decedent (#67) had a history of previous nonintentional methadone overdose occurring 1 week before her final overdose. Six decedents (10%; #6, 16, 27, 28, 34, and 59) had a medical history of prior suicide attempts documented in their medical examiner files. One manner of death (#27) was classified suicide. A history of substance abuse was found in 33 decedents. Eight decedents (#2, 4, 9, 14, 17, 18, 25, and 27) had a history of ever being enrolled in an OTP, although only 3 (#2, 17, and 18) of these decedents were actively enrolled at the time of death. Nine decedents (#26, 33, 35, 37, 42, 55, 56, 67, and 68) exhibited concomitant cocaine use by toxicology.

Source of Methadone

The source of methadone was illicit in 41 (67%) decedents, obtained from an OTP in 3 (5%) decedents, and prescribed by a non-OTP physician in 17 (28%) decedents. Two of the 17 decedents (#6 and 13) with prescriptions by a non-OTP physician had prescriptions found at the death scene, but not in the PMP. There were no cases in which more than 1 source was suggested on the basis of a combination of information obtained from the death investigation and from the PMP and OTP records. Table 1 compares decedents' characteristics by source of methadone.

Illicit Source of Methadone

Forty-one decedents neither had a prescription recorded in the PMP nor were enrolled in an OTP at any time before death and nor had a prescription in their name at the death scene; therefore, the source of methadone was classified as illicit. Decedents with illicit methadone source were younger than those with other sources of methadone (Table 1). For every 1-year increase in age, the odds of illicit source of methadone decreased by 8% (OR = 0.92; 95% confidence interval [CI], 0.86-0.97). Decedents with illicit methadone source were also less likely to have antidepressants found by toxicology (OR = 0.17; 95% CI, 0.05-0.61). Toxicological analysis of decedents with illicit methadone frequently revealed other opioids (OR = 3.27; 95% CI, 0.82-13.0).

OTP Source of Methadone

Three decedents' source of methadone was from an OTP. Two decedents (#2 and 17) with OTP source died within 1 day of their administered dose of methadone. One decedent (#18) died within 2 days of his or her administered dose of methadone. Two of the 3 (#17 and 18) had been prescribed methadone for longer than 1 month. The decedent in the third case (#2) had rejoined the OTP after a short hiatus for a positive urine drug screen for marijuana. The decedent died on the second day of dose reinduction with 30 mg of methadone and the toxicology screen revealed only methadone. Decedent #17 was prescribed methadone 105 mg daily with 2 take-home doses per week and died with methadone and benzodiazepines in her toxicology screen. Decedent #18's dose was not known because the patient was enrolled in an OTP in West Virginia.

Five decedents with a history of OTP enrollment were not actively enrolled at the time of death. Four of the 5 inactive OTP decedents (#4, 9, 14, and 25) died less than 4 months after discharge from an OTP and the longest interval between discharge and a decedent's death was 8 months (#27). Two of the inactive OTP decedents (#4 and 9) were prescribed 6 take-home methadone doses before discharge from the OTP. One of the inactive OTP decedents (#25) had received a prescription for methadone from a non-OTP physician while enrolled in the OTP based on PMP information; however, this prescription was obtained 9 months before death.

Prescription for Methadone in PMP

Individuals prescribed methadone for analgesia were older (OR = 1.16; 95% CI, 1.06-1.26) and more likely to have antidepressants identified by postmortem toxicology (OR = 8.78; 95% CI, 2.3-33.2) than other decedents. None of the decedents with physician prescriptions in the PMP had 6 or more physicians prescribing opioids at one time. Two decedents (#39 and 67) obtained their medications at 4 or more pharmacies. Four decedents (24%) had cocaine in their toxicological analyses (OR = 3.08; 95% CI, 0.67-14.1). Among the 17 decedents with non-OTP physician prescriptions, 14 (82.4%) had a documented chronic pain condition in their medical examiner files.

When decedent prescription dosage was available either at the death scene or from PMP data (n = 9), the range of doses for patients was 20 to 160 mg/d. Four of these decedents were on dosages higher than 40 mg/d and 1 (#8) was simultaneously receiving a prescription for methadone from 2 physicians (1 for 20 mg/d and 1 for 60 mg/d). Five of the methadone prescriptions were initial prescriptions and 2 decedents had sporadically prescribed prescriptions as documented in the PMP.

The majority of deaths in the PMP population occurred around the time of their prescriptions refills. The average number of days from the time of a prescription to a decedent's death was 7 days. In 13 cases (77%), a prescription for methadone was obtained within 7 days of death, and in 8 cases (47%), a prescription for methadone was filled within 4 days of death. Many of these decedents had death scene evidence of large quantities of missing pills from their pill bottles. Medical examiner file information, together with PMP, data provided 1 scenario of the circumstances leading to a decedent's death (#28): the decedent was discharged from a physician's practice because of a positive urine drug screen and secured and filled a prescription for methadone from another physician and died 2 days later.

Discussion

In the current study, 1 of 3 overdose deaths was methadone-related in western Virginia during 2004. Among methadone-related deaths, methadone was more commonly obtained from illicit sources, rather than from physician prescriptions for analgesia or from OTPs. Among those with an analgesic prescription for methadone noted in the PMP, the majority did not exhibit evidence of questionable prescription activity before their deaths. Polysubstance use was common, occurring in two-thirds of methadone-associated deaths.

The methadone deaths described in this article were more numerous than those in prior studies, which had larger base populations and longer follow-up periods (Barrett et al., 1996; Mikolaenko et al., 2002; Ballesteros et al., 2003; Gagajewski and Apple, 2003; Center for Substance Abuse Research, University of Maryland, 2004; Distefano, 2004; Wolf et al., 2004; Shields et al., 2007; Baker and Jenkins, 2008; Paulozzi et al., 2009). The large number of deaths occurring in this small rural region in just 1 year underscores the significance of the problem of methadone-related nonmedical drug use in rural Virginia. This study is also unique in that it provides specific data from 3 OTPs with 1500 patients.

The majority of decedents had no record of methadone prescription or participation in an OTP. This finding is consistent with other studies that reported high rates of illicitly obtained methadone in methadone-related overdose deaths, ranging from 39% to 67% (Barrett et al., 1996; Gagajewski and Apple, 2003; Paulozzi et al., 2009). All of the aforementioned studies collaborated with medical examiner offices and OTPs to help determine circumstances of overdose deaths and participation in methadone maintenance therapy. The more recent study utilized a PMP to determine source of methadone (Paulozzi et al., 2009). The current study extends the results of previous studies by further exploring the source of diverted methadone and characteristics of decedents.

Evidence from this study suggests that the source of diverted medication is varied. Police reports from decedents' medical examiner files corroborated that several patients illicitly bought methadone or obtained methadone from family members. In the 2008 National Survey on Drug Use and Health, 70% of people aged 12 years and older who used pain relievers for nonmedicinal purposes obtained those pain relievers from friends or relatives and only 4% bought them from a drug dealer (SAMHSA, 2009).

For nearly two-thirds of decedents, the cause of death was polysubstance toxicity from an average of 3 substances. The high prevalence of polysubstance-related overdose deaths in this study is similar to that in previous studies (Barrett et al., 1996; Mikolaenko et al., 2002; Oregon Department of Human Services, 2003; Wolf et al., 2004; Hall et al., 2008; Paulozzi et al., 2009; Wunsch et al., 2009) and underscores the need to educate providers, patients, and illicit drug users regarding the increased risk of overdose from enhanced respiratory depression and fatal arrhythmias when combining opioids, sedative hypnotics, and alcohol (Leavitt and Krantz, 2003).

Like other studies, one of the most commonly observed drug combinations was benzodiazepines and methadone (Oregon Department of Human Services, 2003; Wolf et al., 2004; Wunsch et al., 2009). Benzodiazepines, particularly alprazolam, may “boost” the euphoric effects of methadone when taken concomitantly (Stitzer et al., 1981). Methadone and other opioids were also frequently observed in the illicit category. Although the study was underpowered to detect significant differences for this variable, the high proportion of decedents with polyopioid overdose suggests that decedents had access to several illicit opioids. Decedents likely did not appreciate the important pharmacokinetic differences between methadone and other opioids and may have expected it to produce euphoric effects similar to other opioids. We also may hypothesize that the lower cost of both licit and illicit methadone, relative to other opioids (eg, oxycodone or hydromorphone), makes methadone more affordable and easily accessible. Unfortunately, we do not know when or for how long decedents may have been illicitly using methadone, but in many cases the medical examiner information would suggest that decedents were methadone-naive, thus making its delayed toxicity even greater.

Another drug combination observed was cocaine and methadone in 4 of the PMP decedents. These decedents did not have known recent histories of substance abuse treatment that could have placed them at increased risk for overdose death due to lack of tolerance. If cocaine abuse is known at the time of methadone prescription, close physician monitoring is necessary in assessing potential toxic cardiac effects and other forms of substance use. In addition, cocaine is reported to accelerate methadone elimination. Decedents may have therefore taken more methadone than prescribed to achieve adequate pain relief or euphoria (Moolhan et al., 2001).

Our study highlights the importance of previously reported concurrent antidepressants and methadone in overdose deaths (Wunsch et al., 2009). This finding may be particularly salient for older patients who are also at increased risk for methadone overdose deaths from prescribed, instead of illicitly procured, methadone. It has been hypothesized that certain SSRIs and SNRIs may increase the pharmacological effect of methadone by inhibiting its biotransformation in the body (Leavitt, 2005). This drug combination is particularly concerning due to lack of awareness of its potential to increase methadone overdose risk.

Together, the characteristics of the methadone-overdose deaths described in this study are similar to the risk factors reported in heroin overdose (eg, male sex, young age [30s], use of heroin for 10 years, use of heroin alone, lack of enrollment in drug treatment, recent reduction in heroin use, reduced tolerance due to recent release from prison or drug detoxification treatment, injection of heroin, and the use of benzodiazepines, alcohol, or antidepressants (especially tricyclic antidepressants) (Darke and Hall, 2003). Like fatal heroin overdoses, many decedents in this study had a history of substance abuse, most decedents were male, most were not enrolled in drug treatment, and there was a high frequency of polysubstance use.

Finally, this study expands on previous studies that used a PMP to determine source of controlled substances (Hall et al., 2008; Paulozzi et al., 2009). Currently, PMPs exist in 40 states with variable objectives by state; however, the consensus goal of most PMPs is to minimize prescription drug abuse and diversion while supporting legitimate medical practice (Katz et al., 2008; Oregon Department of Human Services, 2009). The few studies to investigate PMP use reported helping providers make informed decisions about opioid prescribing (Katz et al., 2008; Sinha et al., 2009). A key limitation to PMPs is practitioners' infrequent use. Also, patients will cross state lines to avoid monitoring because many PMPs do not report data to other states. Finally, PMPs do not have access to controlled substances obtained from the Internet, OTPs, Department of Veteran's Affairs, or Indian Health Service facilities (US Government Accountability Office, 2009). Interestingly, in this study, there was little PMP evidence of questionable prescription activity in the decedents prescribed methadone, thus raising concern that the PMP may not be an effective method to forewarn prescribers of their patients' potential risk for fatal overdose. Or, it may indicate that the previously described definition of questionable prescription activity is too lenient. Further research is needed to better establish the clinical usefulness of PMP data to aid prescribing practices and predict risk for overdose.

Limitations

This study should be interpreted in the context of several potential limitations. The 61 cases are reviewed from a specified region of the country; they may not be representative of deaths elsewhere. Although rich in detail, the overall small sample size provides limited power to detect statistical differences in trends observed in Tables 1 and 2. Third, because this study depended on toxicology results to identify decedents, it may not comprise a total census of all methadone occurrences in 2004 and may, in fact, underestimate the problem. Finally, the study, in part, depended on a state-sponsored pilot PMP to determine the source of methadone. Therefore, some of the data may be incomplete if all distributing agencies were not involved or if decedents provided false information when obtaining prescriptions. Decedents who were prescribed opioids outside the jurisdiction of the PMP, from OTPs in bordering states, or from the Department of Veteran's Affairs may not have been captured.

Conclusions

This study attempts to determine the source of methadone in overdose deaths and reports rich details about 61 methadone-related deaths. The findings underscore the potential lethality of methadone when used nonmedically, especially when mixed with other psychoactive substances. The study illustrates the difficulty in monitoring the distribution, legal or illegal, of scheduled medications. Finally, the findings disprove our hypothesis that most methadone-related deaths are from physician prescription for analgesia, thus increasing concern about the nonmedical use of methadone. Given the predominance of illicit use of methadone causing overdose deaths, public health interventions may be best targeted to try to reduce diversion or prevent overdose in those who use illicit methadone.

The current study highlights potential risks in those who are prescribed methadone for analgesia: older patients and those who are prescribed, or may illicitly obtain, antidepressants. Physicians should exercise special care when prescribing methadone to these populations. Moreover, given the known risk factor of social isolation and overdose, another aim of overdose prevention in the older population may be the promotion of various outreach programs (eg, communal living or a buddy system). Such measures may reduce the risk of potentially fatal overdose events, particularly when patients for whom they are prescribed misuse their medications.

Finally, physicians may not be able to have an impact upon the problem of illicit methadone abuse, but it is within their grasp to carefully prescribe, monitor, and educate their patients who are prescribed methadone. Patients should be advised to protect prescribed medications by locking them in a safe place and never sharing them. States can aid physicians in this work by providing physicians with regular reports from PMPs that may show signs of diversion or misuse. Further research is needed to measure the effectiveness of PMPs to predict risk for overdose deaths. In addition, continued research combining OCME, PMP, physician, and OTP information may better elucidate risk factors associated with methadone overdose deaths, thus ultimately developing targeted interventions for harm reduction and prevention.

Appendix

TABLE 1. Methadone-overdose decedent characteristics, western Virginia 2004.

	Overall	Source of Methadone
Characteristic	n = 61	Illicit (n = 41)	OTP (n = 3)	Prescription (n = 17)	P-valuea
Mean age, years (SE)	36 (1.3)	33 (1.6)	25 (0.9)	44 (1.6)	<0.001
Gender
Female	22 (36%)	14 (34%)	1 (33%)	7 (41%)	0.875
Race
Caucasian	58 (95%)	38 (93%)	3 (100%)	17 (100%)	0.463
Residence
Rural	27 (44%)	19 (46%)	2 (67%)	6 (35%)	0.539
History of substance abuse	33 (54%)	23 (56%)	3 (100%)	7 (41%)	0.153
Cause of Death
Polysubstance overdose*	37 (61%)	24 (58%)	1 (33%)	12 (71%)	0.424
Concomitant Drugs on Toxicology
Any	47 (77%)	31 (76%)	2 (67%)	14 (82%)	0.778
Antidepressantsb	14 (23%)	5 (12%)	0 (0%)	9 (53%)	0.002
Benzodiazepinesc	22 (36%)	18 (44%)	1 (33%)	3 (18%)	0.165
Other prescribed opiatesd	18 (30%)	15 (37%)	0 (0%)	3 (18%)	0.183
Ethanol	11 (18%)	7 (17%)	1 (33%)	3 (18%)	0.778
Cocainee	8 (13%)	4 (10%)	0 (0%)	4 (24%)	0.290

^aWald x² test obtained from simple linear regression.

^*Drug classes detected include antidepressants, benzodiazepines, opioids, alcohol, and cocaine.

^bAntidepressants include mirtazapine, sertraline, clomipramine, citalopram, amitriptyline, venlafaxine

^cBenzodiazepine parent drug and metabolites include Diazepam, Nordiazepam, Clonazepam, Alprazolam, and Desoxychlordiazepam.

^dOther opiates include hydrocodone, oxycodone, morphine, and hydromorphone.

^eCocaine or cocaine metabolites.