REVIEW ARTICLE

Recommendations for the Investigation, Diagnosis, and

Certification of Deaths Related to Opioid Drugs
Gregory G. Davis MD MSPH and the National Association of Medical Examiners and
American College of Medical Toxicology Expert Panel on Evaluating and Reporting
Opioid Deaths

Gregory G. Davis MD MSPH
is an Associate Coroner/
Medical Examiner at the
Jefferson County Coroner/
Medical Examiner Office and
a Professor of Pathology at
the University of Alabama at
Birmingham.
Contact Dr. Davis at:
gdavis@uab.edu.
Acad Forensic Pathol
2013 3 (1): 62-76
https://doi.org/10.23907/2013.010
© 2017
Academic Forensic Pathology International
ABSTRACT: The American College of Medical Toxicology and the National Association of
Medical Examiners convened an expert panel to generate evidence-based recommendations
for the practice of death investigation and autopsy, toxicological analysis, interpretation of the
toxicology findings, and death certification to improve the precision of death certificate data
available for public health surveillance. The panel finds the following:
1. A complete autopsy is necessary for optimal interpretation of toxicology results, which
must also be considered in the context of the circumstances surrounding death, medical
history, and scene findings.
2. A complete scene investigation extends to reconciliation of prescription information and
pill counts.
3. Blood, urine, and vitreous humor, when available, should be retained in all cases. Blood
from the femoral vein is preferable to blood from other sites.
4. A toxicological panel should be comprehensive and include opioid and benzodiazepine
analytes, as well as other potent depressant, stimulant, and antidepressant medications.
5. Interpretation of postmortem opioid concentrations requires correlation with medical
history, scene investigation, and autopsy findings.
6. If death is attributed to any drug or combination of drugs (whether as cause or
contributing factor), the certifier should list all the responsible substances by generic
name in the autopsy report and on the death certificate.
7. The best classification for manner in deaths due to the misuse or abuse of opioids without
any apparent intent of self-harm is “accident.” Reserve “undetermined” as the manner for
the rare cases in which evidence exists to support more than one possible determination.
KEYWORDS: Forensic pathology, Forensic toxicology, Medical toxicology, Opioid, Opiate, Death certification, Autopsy, Drug abuse,
Surveillance, Public health, Postmortem

INTRODUCTION for pain relief are called opioid analgesics (1).

The term “opioid” in this document refers to
any substance that stimulates the body’s opioid
receptors, whether that substance is naturally
derived (e.g., morphine, codeine), semisynthetic
(e.g., hydrocodone, oxycodone), or synthetic
Page 62 • Volume 3 Issue 1
Since 1999, the number of intoxication deaths
involving opioid analgesics in the United States
has quadrupled (2), reaching 16,651 deaths in
2010 (3) and surpassing the combined total of in-
toxication deaths involving heroin or cocaine (4).
These data are derived from death certificates,

(e.g., methadone, fentanyl). Opioids marketed but the contribution of opioid analgesics to the
38,000 drug-related deaths in the United States
is even greater than such data suggest, because
death certificates frequently do not specify the
type of drug involved in drug poisoning deaths
in the United States (2, 3). For example, certify-
ing the cause of death as “mixed drug intoxica-
tion” provides no insight into what specific drugs
included medical subject heading (MeSH) terms
related to opioids/opiates, mortality, toxicology,
autopsy, and death certificates (Appendix). The
panel’s consensus was to limit the search to Eng-
lish language articles about humans published in
the last 20 years, with the opioid-related concepts
listed above designated as major subject head-

OPIOID DEATH TECHNICAL REPORT

composed the mix if no specific drug is listed
by name. In addition, individual jurisdictions
vary widely in the degree to which they docu-
ment specific drugs (5). (Note that “poisoning”
and “intoxication” are used synonymously in this
paper).
In 2012, the American College of Medical Toxi-
cology (ACMT) and the National Association of
Medical Examiners (NAME), with financial sup-
port provided by the Centers for Disease Control
and Prevention (CDC), convened an expert panel
consisting of pathologists and toxicologists to ad-
dress death investigation and certification of opi-
oid drug related deaths. This panel systematically
reviewed the peer-reviewed literature regarding
the topic of fatal opioid analgesic poisoning. The
intent of this panel was to develop evidence-
based recommendations for the practice of death
investigation and autopsy, toxicological analysis,
interpretation of those analyses, and death certi-
fication, in order to better inform public health
surveillance and epidemiologic efforts. The pan-
el formulated six questions designed to address
best practices and searched the literature to pro-
vide evidence to support those practices (Table
1). These questions are arranged in the order that
they would arise during the investigation of a
death. The panel submitted a position paper to
the Boards of Directors of ACMT and NAME,
and each society endorsed that position paper (6).
This article provides details of the development
of the questions, the level of evidence available
in the medical literature, and additional data that
support the position paper.
Prior to the panel’s meeting, a health sciences li-
brarian (GGH) searched PubMed for articles rele-
vant to opioid-related deaths, using the questions
developed by the panel. The search strategies
ings. Using these criteria, the librarian retrieved
217 articles. A search in the National Criminal
Justice Reference Service Database yielded 23
additional citations. The principal investigator
(KBN) performed a preliminary review of the
240 articles and identified 122 articles to be re-
viewed by panel members. The articles generally
consisted of review articles, case-control studies,
or case series reviews, as is typical for the pa-
thology literature. In reviewing the articles, the
panel members commented upon the pertinence
of the article to answering each of the six ques-
tions. Automatic search updates (from the Na-
tional Center for Biotechnology Information),
more targeted searches, and recommendations
from panel members increased the number of
articles considered. Ultimately, 227 articles were
reviewed for the guidelines and manuscript.
1. Within the bounds of state law, which
deaths require assumption of jurisdiction
and performance of an autopsy?
Scene findings suggestive of opioid use or ab-
sence of a history of opioid use are unreliable
predictors of intoxication in forensic pathol-
ogy practice (7, 8). This is especially true for
opioid analgesic poisonings because decedents
frequently lack a history of any prescription for
opioids (9). Conversely, the use of opioids is so
prevalent that many people dying of other causes
have a history of opioid use (10). Consequently,
the panel recommends that medical examin-
ers and coroners (ME/Cs) assume jurisdiction
of cases where the death is unexpected or un-
explained and the person was in apparent good
health, or when the death is known or suspected
to be unnatural (e.g., fatal intoxication) (11).
The autopsy provides the most accurate means

Table 1: List of Questions Used to Improve Quality of Death Investigation in Opioid Deaths
1. Within the bounds of state law, which deaths require assumption of jurisdiction and performance of an autopsy?

2. What constitutes appropriate and necessary scene investigation?

3. When is it appropriate or necessary to perform toxicology testing?

4. What are the best techniques for specimen collection and what should be the scope of the toxicological analysis?

5. How does the interpretation of postmortem drug concentrations affect the certification of deaths related to opioids?

What are the optimal methods for determining and recording (certifying) cause of death, manner of death, and how
6. injury occurred (including wording on the death certificate)?
Davis et al. • Page 63
 of determining the cause of death (12). External
examination, even including blood sampling for
toxicology, is an inadequate substitute for au-
REVIEW ARTICLE
topsy for the purposes of detecting and certifying
drug-related deaths because autopsy findings can
support or exclude intoxication as the cause of
death (13). Therefore, the panel recommends that
a ME/C assume jurisdiction and perform an au-
topsy to determine the cause and manner of death
whenever intoxication is reasonably suspected as
a possible cause of death. NAME Autopsy Per-
formance Standards also recommend that an au-
topsy be performed whenever intoxication is sus-
pected (11). Because autopsy is the examination
necessary to meet the proper standard of practice
in suspected intoxication deaths, the panel rec-
ommends that a ME/C office receive sufficient
funding and personnel to meet this standard. Lo-
cal laws governing jurisdiction might also influ-
ence which cases receive autopsies (11).
The panel recognizes that many intravenous drug
abusers are infected with blood-borne pathogens
(e.g., Hepatitis C or Human Immunodeficiency
Virus) (14), but proper precautions allow those
performing the autopsy and toxicological analy-
sis to minimize the risk of infection (15), and thus
concern regarding contracting an infectious dis-
ease while performing an autopsy in these cases
is an inadequate reason to avoid internal autopsy
examinations. External examination is an inad-
equate substitute for autopsy for the purposes of
detecting and certifying drug caused deaths. The
panel recommends that whenever a ME/C assumes
jurisdiction in a death, the ME/C should also seek
and assume jurisdiction over any laboratory speci-
mens such as blood, serum, and urine obtained
prior to death by medical professionals (16).
Table 2: Examples of Scene Findings Suggesting Opioid Misuse or Abuse
Opioid medications
History of methadone use
Evidence of intravenous drug abuse (e.g., needles, cooker spoons, tourniquet, crushed tablets, packets of powder or crystals,
other drug paraphernalia)
Overlapping prescriptions for the same type of prescribed controlled substances; prescriptions for controlled substances
from multiple pharmacies or multiple prescribers
Prescriptions in other people’s names
Pills not stored in prescription vials or mixed in vials
Injection sites not due to resuscitation attempts
Altered transdermal patches
Many transdermal patches on body or transdermal patches in unusual locations, (e.g., mouth, stomach, vagina, or rectum)
Application of heat to increase the rate of transfer of drug from transdermal patch to decedent
Page 64 • Volume 3 Issue 1
Presence of naloxone
2. What constitutes appropriate and necessary
scene investigation?
The expert panel supports the practices recom-
mended in the 2011 USDOJ National Institute
of Justice (NIJ) Death Investigation Guidelines
published by the United States Department of
Justice (17). Other excellent general guidelines
for scene investigation are readily available (18).
The panel concurs with the investigative guide-
lines calling for an investigator and ME/C to
look for evidence of drug use, misuse, or abuse;
examples are listed in Table 2. The presence of
recent needle marks can be strongly predictive of
intoxication (19), but the presence of prescription
vials may not be predictive. The absence of drugs
or paraphernalia, however, has a low predictive
value (9). The best practice of investigation in-
cludes seeking evidence of use of medications,
illicit drugs, or both. Therefore, the ME/C should
document any medical therapy, both at the scene
in the form of acute attempts at resuscitation (e.g.,
injection sites for intravenous access, naloxone
administration) and subsequently in the form of
medical and prescription records concerning the
decedent’s medical history.
The panel recommends taking an inventory of all
medications found at the scene. This inventory
provides important information to both patholo-
gists and toxicologists. For opioid analgesics,
comparison of the number of tablets or amount
of medication dispensed with the stated admin-
istration regimen and number of pills remaining
at the time of death can provide useful informa-
tion for the determination of the cause and man-
ner of death and may direct toxicology testing. A
medication log provides a concise means for in-
vestigators to record the necessary information,
making it easier to assess appropriate use, over-
use, or underutilization of prescription drugs.
The examination of medications also provides
general information about medical history that
may not be otherwise immediately available and
that may relate to the potential for opioid related
death, for example, finding both long standing
medications for chronic obstructive pulmonary
disease and a new prescription for an opioid
(from an emergency department) at the investi-
gative scene. A medication log, whether in the
form of a table, spreadsheet or database, includes
all of the medications’ names, dosing informa-
tion, amount prescribed, amount remaining, refill
number, dates that the prescriptions were filled,
and the prescriber information (Figure 1). This
information can aid in the eventual interpreta-
tion of postmortem concentrations. For example,
finding multiple refills spanning a long period of
time suggests the possibility that tolerance may
have developed, whereas finding multiple prac-
titioners prescribing overlapping dosages of con-
trolled drugs with similar effects or synergistic
effects suggests chronic abuse and “doctor shop-
ping.” Medication container contents should be
visually examined for verification and determi-
nation if pills are mixed or altered. Jurisdictions
may differ in the approach to this inventory of
medications. Digital photography can effectively
document medications at scenes (20). Pill bottle
labels and contents can be photographed, and
then counted on scene, without taking physical
custody of medications. Attempts to manipulate
opioids, such as tablets that have been crushed or
otherwise altered, should be noted as indications
of misuse. An office should have a procedure for
the appropriate disposal of those drugs that are
retained as evidence in a given case, once the evi-
dence is no longer needed.
Unlike pills that are ingested and quickly dis-
solved, transdermal patches for opioid delivery
are often found still attached to the body. Users
can intentionally or inadvertently alter the release
of drug from a transdermal patch, possibly lead-
Case:
Date of death:
Rx No. Medication Dose (mg) Pharmacy Phone
xxxx diazepam 10
yyyy oxycodone 30
zzzz atenolol 50
Figure 1: Example of a spreadsheet useful for tabulating medications found at a scene. With appropriate additions, this sheet
can also include information obtained from a prescription drug monitoring program or simultaneously serve as a transfer of
evidence form.
ing to death, and manufacturers may be subject
to civil litigation based on allegations of manu-
facturing defects and recalls (21). For all these
reasons, transdermal patches require special han-
dling as evidence.
The panel recommends that the scene investiga-
OPIOID DEATH TECHNICAL REPORT
tor describe and record the patch prescription
information, including manufacturer; lot num-
ber; and numbers of patches remaining at the
scene. Document any evidence at the scene that
the patch was used in a manner that would in-
crease drug delivery, whether across skin (e.g.,
tanning salon, hot tub, or heating pad) or through
mucosa (e.g., chewing or swallowing patch).
Inspect the oral cavity and gastric contents of
patch users carefully, especially if patch counts
are discordant at the scene, as abusers may in-
gest the patches. During examination, it is im-
portant to record the position of the patch on the
body, ideally photographing it both in situ and
after removal (22). The pathologist should note
any residue on the body, or folds or defects on
the patch, and comment on the integrity of the
underlying skin. Because of the potential for
criminal or civil litigation, any defects noted in
the integrity of a patch may require further in-
vestigation at a later time. Regardless of whether
a defect is visible or not, the panel recommends
retaining the patches removed from the body as
evidence because allegations of patch malfunc-
tion are common. Placing used patches in a clear
round container, with the sticky side on the inside
and away from the walls of the container, allows
for the best preservation of the patch for subse-
quent inspection. Affixing the adhesive surface
of fentanyl patches onto paper or heat sealing
them in plastic can damage the adhesive surface
and compromise patch integrity, compromising
the utility of material science examination for
manufacturer defects.
Patient Controlled Analgesia (PCA) pumps or
indwelling catheters or analgesic implants in a
drug-related death require special investigations
and procedures. A PCA pump can be queried
Decedent’s name:
Aliases:
Prescriber Date filled Quantity Left Refills Instructions
90 37 1 tab TID
90 0 1 tab q8h
30 22 1 tablet qd
Davis et al. • Page 65
 for loading doses, administration schedule, and
remaining drug in the reservoir. Anesthesia spe-
cialists and clinical pharmacists can help obtain
REVIEW ARTICLE
information from the pump. Due to the risk of
loss of potential useful evidence in a hospital
death associated with use of a PCA pump, inves-
tigation should include requests of hospitals to
maintain pumps and associated bags containing
the delivered medication. Human operator error
is a common cause of malfunction of PCA pumps
(23, 24). The examination of the pumps is tech-
nically demanding and beyond the scope of this
paper.
If possible and allowed by law, the investiga-
tor should seek information on the number and
timing of prescriptions for controlled substances
received from state prescription drug monitoring
programs (PDMP). Though 43 states have opera-
tional PDMPs (as of November, 2012), organiza-
tion and operation of PDMPs varies among states
in important details such as which controlled
substances must be reported, who has access to
the data, and which medication dispensers are
required to submit data (25). Some states restrict
access to physicians who are treating a given pa-
tient. Because PDMP have information that can
be useful in the evaluation of deaths where opioid
drugs are detected, the panel recommends that
ME/Cs have access to the information available
in prescription drug monitoring programs both
in the decedent’s state and across state lines. As
of September, 2012, only twelve states provided
PDMP data to coroners and/or medical examin-
ers (26). Currently, there are no national level re-
quirements for either uniformity in PDMP data
or interoperability.
3. When is it appropriate or necessary to
perform toxicology testing?
In the absence of constraints on funding, resourc-
es, or time, a ME/C would ideally conduct toxi-
cology testing on all decedents, because the com-
bination of history, investigative information,
and autopsy is an insensitive indicator of drug
intoxication (7, 8). Some forensic ME/C offices
have found it useful to assess cases at the time
of autopsy for the presence of drugs based on a
quick screening test of urine with a kit (8, 27).
Screening tests alone offer only weak evidence,
are subject to clinical and analytical false nega-
tives, and are inadequate for establishing a cause
of death (8, 27). Because constraints on resources
are common in forensic practice, the panel rec-
ommends performing toxicological analysis for
controlled substances on all decedents for whom
one or more of the following conditions are true:
Page 66 • Volume 3 Issue 1
1. Known history of prescription opioid or illicit
drug use, misuse, or abuse (28);
2. Evidence of prescription opioid or illicit drug
abuse revealed by scene investigation;
3. Autopsy findings suggesting a history of
illicit drug abuse (e.g., needle marks, hepatic
cirrhosis, and cases in which birefringent
crystalline material is within foreign body
giant cells in the lungs);
4. Massive lung edema and froth in airways
with no grossly visible explanation (e.g., heart
disease) or other non-toxicological explana-
tion (e.g., epileptic seizure) (29);
5. Potential or suspected smugglers of illicit
drugs (mules) (30);
6. No unequivocal cause for death identified at
autopsy;
7. Decedents with a potential natural cause of
death visible at autopsy whenever a drug may
have precipitated or contributed to death by
an additive mechanism, such as opioid-
induced respiratory depression in a decedent
with emphysema; or
8. Traumatic deaths. (Such testing can provide
information concerning a factor that may have
contributed to death, thereby allowing better
measurement of the total social burden of
drug use and helping resolve questions that
arise later in legal proceedings (7). For exam-
ple, identification of methadone in the blood
of a driver who sustains an open skull fracture
in a motor vehicle crash may provide an
explanation for the driver’s failure to negoti-
ate a sharp curve in the road).
4. What are the best techniques for specimen
collection and what should be the scope of
the toxicological analysis?
Factors such as delay in autopsy, sampling tech-
nique, and specimen preservation contribute
more to inaccuracies associated with toxicologi-
cal testing than do the testing procedures them-
selves (31), but procuring and storing toxicology
specimens under optimal conditions mitigate
these factors (16, 32). The NAME standards call
for collection of blood, urine, and vitreous humor
as toxicology specimens in all cases, provided
these specimens are available (11). Specimens
that may be particularly relevant to deaths related
to opioids include blood, vitreous humor, urine
(or bile when urine is not available), and gastric
contents. In cases of decomposing remains, de-
composing tissue, preferably deep tissue such as
liver or brain, should be taken as a toxicology
specimen. Decomposition fluid is not a recom-
mended specimen due to lack of interpretive
value. Literature that provides evidence-based
guidance in the interpretation of concentrations
in decomposing tissue is lacking. The interpreta-
tion of postmortem concentrations is discussed at
ity (16). Blood obtained from a body cavity is
a specimen of last resort. Useful specimens are
shown in Table 3.
Label each specimen as accurately as possible
regarding the anatomical source of the specimen
(e.g., “blood from femoral vein”, not “blood”)

OPIOID DEATH TECHNICAL REPORT

greater length under Question 5.
Because of postmortem redistribution of drugs,
the best source of a blood sample for toxico-
logical analysis is the ilio-femoral vein (16, 32).
Although some offices ligate the femoral vein
and draw distal to the ligation under direct visu-
alization, at least one study shows that samples
drawn by blind stick access to the femoral vein
yield closely comparable concentrations (33). If
femoral vein blood is not available, then blood
from the subclavian vein, the right atrium of the
heart, or any other intact blood vessel is the next
choice, listed in decreasing order of desirabil-
and document transfer of specimens with an ap-
propriate chain of custody. Circumstances may
make one specimen more relevant than others
(e.g., gastric contents when there is a suicide note
and empty pill bottles). Store specimens in tightly
sealed containers at 4°C for short-term storage.
Consult with the analytical toxicologist who
will be performing the toxicological analyses for
guidance concerning longer storage. Sodium oxa-
late and sodium fluoride are the anticoagulant and
preservative, respectively, of choice for blood in
routine cases. Articles summarize and detail spec-
imen selection, collection, and storage (16, 32).

Table 3: Comments Regarding Various Toxicological Matrices (note that list is not exhaustive)
Fluid / Tissue General Utility Opioid-Specific Utility

Matrix for which most toxicological data exist. Sub- Matrix for which most opioid data exist. For mor-
Blood ject to postmortem redistribution of drug, particular- phine, results should indicate whether reported
(postmortem) ly when obtained from central sites. Best specimen concentration is for free or total morphine.
is obtained from ilio-femoral vein.

Best specimen for analysis of ethanol if body has

entered an early stage of decomposition. Time 6-acetylmorphine persists longer in vitreous
Vitreous humor delay between blood concentrations and entrance humor than in blood.
into vitreous must be considered. Best specimen for
postmortem glucose determination.

Must be recognized that many opioids exist

mainly as conjugates in urine. Ensure laboratory
Fluid where certain drugs, drug metabolites and
Urine uses methods to account for conjugates. Opioids
other toxicants accumulate. and opioid metabolites are found in high concen-
tration.

Opioids are generally stored or conjugated in

Fluid where certain drugs, drug metabolites and oth- bile, thus the presence of an opioid demonstrates
Bile er toxicants accumulate. Generally associated with exposure. Presence is not necessarily correlated
substances that are eliminated fecally. to time of exposure, especially in chronic users.

Organ of high concentration for many xenobiotics.

Large blood flow, first pass effects, and other fac-
tors result in accumulation of substances in the liver.
Liver Care must be taken in interpreting liver concentra-
tions as they may be influenced by a number of fac-
tors (e.g., postmortem diffusion and redistribution).
May assist in interpretation of blood findings
for some substances. Can demonstrate exposure
to an opioid in the absence of such findings in
blood.

Some reports of correlation to effects, however, data Potentially useful when blood is not readily
Brain are equivocal. A difficult specimen to handle analyti- available, correlations of some opioids to blood
cally due to its fat content. concentrations have been made (34).

As tolerance is a significant issue in assessing

Provides data related to exposure history through the potential effects of opioids, use patterns over
Hair segmental analysis. Limitations may include exter- time as demonstrated by segmental analysis may
nal contamination and hair color bias. assist in the interpretation of opioid findings.

As an organ associated with elimination, opioids

Many toxicants accumulate in kidney due to both may accumulate in kidney, even in the absence of
Kidney nonspecific and specific binding. blood findings. Correlation to blood concentra-
tions may be poor.

Useful in some circumstances, particularly to as-

Gastric contents sess for ingestion of inappropriate number of pills.
Davis et al. • Page 67

An adequate analyte panel for opioid
substances includes all common opioid
REVIEW ARTICLE
analytes, including but not necessarily
limited to those listed below (although
propoxyphene is no longer sold, it does still
exist):
Buprenorphine
Codeine
Fentanyl
Hydrocodone
Hydromorphone
Meperidine
Methadone
6-Acetylmorphine
Morphine
Oxycodone
Oxymorphone
Propoxyphene
Tapentadol
Tramadol
An analyte panel should also include other
medications such as:
Benzodiazepines
Antidepressants
Muscle relaxants
Sleep aids
Ethanol
Stimulants (both pharmaceutical and illicit)
Obviously, this list will change over time as
pharmaceutical companies develop and mar-
ket new drugs or cease production of a drug
that is currently available.
Evidence of drug use or abuse sometimes accom-
panies bodies into the morgue in the form of pills,
patches, syringes, or packets of drugs. Drugs may
be found in clothing or in body cavities. Clothing
should be searched carefully in order to avoid
needle stick injuries. The mere presence of a sub-
stance in a pocket does not necessarily predict
the detection of that substance in the body. Nev-
ertheless, such evidence is useful during a death
investigation. The toxicology laboratory needs to
know what evidence was found, and the lab may
also request samples of the substances found.
5. How does the interpretation of postmortem
drug concentrations affect the certification
of deaths related to opioids?
Postmortem drug concentrations are useful, even
essential, in the determination of cause of death,
but toxicological test results must be interpreted
in the context of the circumstances surrounding
Page 68 • Volume 3 Issue 1
death, the medical history, the scene of the death,
and the autopsy findings, including the time
elapsed between death and sample collection (35,
36). A ME/C must use caution when relying on
case studies and published tables of toxicology
results, as tables are often based on a few cases
and provide little or no contextual information
about specific case details (e.g., clinical circum-
stances, recent controlled substance dose adjust-
ments, extent of opioid tolerance, drug-drug in-
teractions, postmortem interval, scene findings,
site of sample collection, co-intoxicants, autopsy
findings). Given the proper circumstances and
autopsy findings, a drug can cause death even at
a concentration below what some consider a re-
ported lethal range. Conversely, the simple pres-
ence of a drug concentration within the reported
lethal range does not necessarily make the drug
the cause of death. Correct interpretation again
depends on knowledge of the circumstances
surrounding death and the findings at autopsy,
particularly for drugs with a narrow therapeu-
tic range (28). Drug concentrations measured
in postmortem blood samples cannot be used to
reliably calculate the precise quantity of medica-
tion consumed (37).
Postmortem redistribution (PMR) is a long-es-
tablished principle in forensic toxicology (38).
This phenomenon results in changes in concen-
trations of drugs and other toxicants at various
anatomical sites after death, especially in heart
blood. Many factors can hasten or retard the like-
lihood of such an occurrence. Passive release
of drugs from relative drug reservoirs, such as
the gastrointestinal tract, liver, lungs, heart, or
fat can alter the concentration of drug in blood
that is no longer actively circulating. Autolysis
and putrefaction may alter the chemical environ-
ment and destroy barriers at the cellular or gross
level (e.g., gastromalacia), contributing further to
postmortem redistribution. If, for example, these
changes lead to additional drug release into the
biological matrix sampled for toxicological test-
ing, then the postmortem drug concentration may
be falsely elevated with respect to the antemor-
tem concentration. Alternatively, if these changes
alter the drug chemically, then the postmortem
concentration may be falsely decreased. Reviews
describe these factors in more detail (39, 40). At-
tempting to predict the role of PMR in a given
case is unwarranted, because striking variations
in reported drug concentrations from site to site
prevent reliance on this data (41). Although PMR
can occur, it is unpredictable in magnitude and
direction and may not occur in every case. Nev-
ertheless, a ME/C can generally make reasoned,
clear, and defensible determinations of the cause
and manner of death by using sound judgment
based on the complete investigative and autopsy
findings. In other words, the existence of PMR
should not be used as an excuse to avoid making
decisions concerning cause and manner of death
in cases with toxicological findings.
Tolerance accounts for some of the overlap be-
tween therapeutic, supratherapeutic, and lethal
concentrations of opioid analgesics observed
in decedents, complicating the interpretation of
postmortem concentrations of opioids and oth-
er drugs (22, 40). Note that there is no reliable
quantifiable measure of drug tolerance before
or after death other than empiric evidence based
on the dose actually taken and tolerated, which
is often unknown. Information from relatives or
friends of the decedent and the decedent’s medi-
cal records, pharmacy records, and state pre-
scription drug monitoring programs may all help
assess whether tolerance is likely, but this is at
best a rough guide with many potential limita-
tions. Many people who die of prescription opi-
oid intoxication do not have a prescription in the
PDMP for one or more drugs detected at autopsy
(9). Other factors must also be considered when
evaluating toxicological findings in assessing
potential tolerance (42), such as loss of toler-
ance during incarceration or hospitalization, or
the possibility that individuals sometimes divert
rather than ingest the drugs prescribed to them
(9). Research suggests that tolerance to the re-
spiratory depression caused by opioids develops
more slowly and less completely than tolerance
to the intoxicating effects of opioids, so that
continued abuse of opioids brings an individual
seeking a high increasingly closer to the point of
fatal respiratory depression (43). Because there
is no reliable quantifiable measure of tolerance,
tolerance is important as a consideration but dif-
ficult to apply to a specific case except as a gen-
eral concept.
Drug-drug or drug-toxicant interactions are com-
plex and can occur on two levels – pharmacoki-
netic and pharmacodynamic (44). These complex
interactions can contribute to the development of
adverse effects from an opioid. Pharmacokinet-
ic interactions arise when one co-administered
agent interferes with the absorption, distribution,
metabolism, or elimination of another by one or
more mechanisms such as competitive inhibition
of metabolic enzymes. Pharmacodynamic inter-
actions refer to the effect of drugs on an indi-
vidual; these effects are related to the combined
clinical effects of the substances, resulting in an
increased, decreased, or different clinical effect
of the target drug, as may occur when two cen-
tral nervous system depressant-type substances
(e.g., a benzodiazepine and an opioid) result in
at least an additive effect. Because many vari-
ables determine whether any interactions occur,
no a priori method can determine whether any
interaction occurred in a given case; this should
not, however, preclude consideration of potential
interactions with respect to cause of death deter-
mination.
Determination of the cause of death should ac-
count for pathways of drug metabolism (Figure
OPIOID DEATH TECHNICAL REPORT
2). Given that heroin is metabolized rapidly to
6-acetylmorphine (6-AM), the presence of 6-AM
rather than heroin is sufficient to ascribe intoxi-
cation to heroin. Laboratories should take pre-
caution not to use analytical methods that pro-
duce unintended consequences (e.g., using an
extraction technique that acetylates morphine to
6-AM or heroin). In the absence of 6-AM, heroin
use can be reasonably inferred by other means.
For example, pure morphine could come from
the ingestion of morphine or as a metabolite of
codeine. In heroin, however, codeine from the
opium derived from poppies is present as a slight
contaminant, and so a morphine:codeine ratio
greater than one may be considered as evidence
of heroin use, and thus the cause of death can be
ascribed to heroin use (45, 46).
If heroin use is suspected, and blood analysis
does not yield supporting evidence of heroin
use, analysis of urine and vitreous humor may
reveal 6-AM, which persists in urine and vitre-
ous humor longer than it persists in blood. Other
opioids found in postmortem specimens must
also be interpreted carefully in light of metabolic
processes. For example, hydromorphone and hy-
drocodone may be the result of morphine and co-
deine administration, respectively (47).
The concentration of drugs in solid tissues should
be interpreted cautiously, because the data con-
cerning solid organ drug concentrations are gen-
erally sparse and highly variable (16, 32). Drugs
may distribute unevenly throughout organs such
as the liver or brain because of variations in
blood flow, bioaccumulation, and other factors,
which further complicate interpretation (48-50).
With certain organs (e.g., liver), a large breadth
of data is available for some drugs, and such data
have been used to assess intoxication, but always
within the context of the case (16, 32). Interpre-
tation of solid tissue concentrations of drugs is
complicated, and often impossible beyond quali-
tative evidence of exposure.
Pharmacogenomics is a developing science with
respect to drug or toxicant effects. Current labo-
ratory analyses can identify polymorphisms of
key metabolic enzymes, such as the cytochrome
P450 (CYP) genes (51-53). Such polymorphisms
may alter the pharmacokinetic or pharmaco-
dynamic profile of a drug, including opioids,
thereby altering associated clinical effects of that
Davis et al. • Page 69
REVIEW ARTICLE

13 -14%

3%
Dihydrocodeine Oxycodone Oxymorphone
Minor

~5%

Hydrocodone Heroin
Minor
Hydromorphone
100%

Minor

Codeine 6-acetylmorphine
5-13%
100%

Morphine

Figure 2: Opioid metabolism: O-demethylation of codeine to morphine is influenced by cytochrome P450 (CYP) 2D6 geno-
types, as is conversion of hydrocodone to hydromorphone. The synthetic oxidized derivative of codeine, oxycodone, is
similarly O-demethylated to oxymorphone. Minor metabolic conversion of codeine and dihydrocodeine to hydrocodone has
been described, as well as reduction of hydrocodone to dihydrocodeine. Metabolism of morphine to hydromorphone has
been described in several reports and appears to be a minor pathway (<3%). Adapted from Bioanalysis, August 2009, Vol. 1,
No. 5, Pages 937-995, with permission of Future Science Ltd.

drug (54). The broad-based utility of such test-
ing is still not fully established, in part because
genotype does not necessarily correlate directly
with phenotype. Phenotype can be influenced
by a number of independent variables, includ-
ing environmental factors and alternative meta-
bolic routes (55). Nevertheless, in select cases,
pharmacogenomic analysis may provide useful
information in addressing a specific issue; such
analysis would require saving a tube of blood
preserved in EDTA (purple top tube) (56).
6. What are the optimal methods for deter-
mining and recording (certifying) cause of
death, manner of death, and how injury
occurred (including wording on the death
certificate)?
Death certificate data are often used to deter-
mine priorities in public health. Four sections
of the death certificate are particularly impor-
tant to nosologists (who code death certificate
data) and those who conduct research and public
health work on opioid-related deaths – Cause of
Death, Other Significant Conditions Contribut-
Page 70 • Volume 3 Issue 1
labeled “Describe How Injury Occurred.” Death
certificates must be completed and filed as soon
as possible following death, and completion is
sometimes necessary before toxicology results
become available. Nevertheless, in order to
maximize useful information about opioid drug
deaths, the panel recommends that the death
certificate be completed with the most specific
details available about a given death. In juris-
dictions that require the death certificate be filed
before pertinent toxicology results are available,
then certificates can be filed as “pending” and
amended later to the appropriate cause and man-
ner of death after the toxicology results are avail-
able. Any case in which toxicology results would
change the cause or manner of death should also
be amended; for example, a death attributed to
coronary artery atherosclerosis with no more
than 50% narrowing of the coronary arteries by
plaque in which toxicology testing subsequently
reveals an unexpected and high concentration of
hydrocodone. In this example, the cause of death
would be amended to hydrocodone intoxication
with the coronary artery atherosclerosis contrib-
uting to, rather than causing, death.

ing to Death, Manner of Death, and the section

Cause of Death
Different countries adopt distinct approaches
to attributing death to a drug or drugs. Some
in the United States have recognized a lack of
standardization of definitions, interpretation, and
diagnosis of opioid deaths (57, 58). Therefore,
this panel offers a standardized approach for
certifying these deaths in the United States. The
panel recommends listing all the drugs deemed
as causal or contributory based on the ME/C’s
judgment (59, 60). List the generic name of all
of the chemical agents in the autopsy report and
on the death certificate. Avoid vague, nonspecific
descriptions such as “mixed drug intoxication”
or “polypharmacy” in the absence of a list of the
specific substances that caused death. (Nosolo-
gists code substances that cause death as spe-
cifically as possible, based on the level of detail
provided on the death certificate. Incomplete or
vague information on death certificates prevents
accurate measurement of the magnitude of drug
related deaths, thus hampering assessment of the
need for public health interventions and evalua-
tion of any instituted interventions).
The recommended approach applies to drugs
present in concentrations that the pathologist
considers sufficient to have caused death in a
given case, understanding the limitations of
drug concentration interpretation previously de-
scribed. The recommended approach also applies
to those cases where several drugs are each pres-
ent in a concentration that might be considered
sublethal, but the circumstances surrounding
death and the autopsy findings make clear that
the aggregate effect of these drugs caused or con-
tributed to death. If a drug is present but does
not play any role in death, then the panel recom-
mends not mentioning the drug on the death cer-
tificate. Drugs administered in resuscitation at-
tempts should not be included unless those drugs
specifically led to death.
An example may clarify the recommendations in
the previous paragraph. A 27-year-old decedent
with a history of opioid abuse was heard “snoring
loudly” and later found unresponsive. Autopsy
showed no visible disease or injury. Toxicologi-
cal analysis of blood from the iliac veins detect-
ed ethanol (0.21 g/dL), methadone (0.22 mg/L),
hydrocodone (0.06 mg/L), acetaminophen (<10
mg/L), and nicotine (not quantified). In this case,
progressively deeper respiratory depression has
led to death. Methadone, hydrocodone, and etha-
nol all act as central nervous system and respira-
tory depressants, and their pharmacodynamic in-
teraction caused death. Consequently, the cause
of death statement would include the intoxicants
methadone, hydrocodone, and ethanol. Neither
acetaminophen nor nicotine is a depressant, and
they did not cause or contribute to death because
they do not potentiate lethal respiratory depres-
sion. Therefore, neither acetaminophen nor nico-
tine is mentioned on the death certificate.
Use of phrases such as “abuse,” “addiction,” or
OPIOID DEATH TECHNICAL REPORT
“misuse” in the cause of death section may result
in the classification of the death as due to drug
abuse, which is classified as a mental disorder in
the International Classification of Diseases. The
death may therefore be tabulated among natural
causes of death rather than “Accident,” “Sui-
cide,” or “Homicide.” If the ME/C believes the
death is properly attributed to a chronic process,
then use of such terms is appropriate. If, how-
ever, the ME/C believes death resulted from an
acute intoxication or poisoning, then including
terms such as “poisoning,” intoxication,” “toxic-
ity,” or “overdose” will result in a more accurate
classification of the cause of death.
Other Significant Conditions
In this section, also referred to as “Part II” of the
Cause of Death, list conditions that might have
predisposed the person to death but which were
neither necessary nor sufficient to cause death.
For example, obstructive sleep apnea might con-
tribute to death from an opioid overdose without
being the underlying cause of death. The recom-
mendations for specificity in wording the cause
of death also apply to listing contributing factors.
Manner of Death
In the US in 2008, over three quarters of the
drug intoxication deaths were certified as acci-
dents, about 15% were certified as suicides, and
the remaining deaths, approximately 10%, were
certified with an undetermined manner (2). Death
certificate data show that the states vary widely
on the manners of death assigned to drug deaths,
particularly, the undetermined manner. For in-
stance, in three states, over a third of these deaths
were certified as undetermined in 2004 (61). This
wide variation suggests that there are inconsis-
tencies in certification protocols rather than a real
difference in available evidence.
Drug-related deaths are often complex, requir-
ing thorough investigation (e.g., interviews with
family and friends of the decedent, review of a
decedent’s diary or social networking pages, fam-
ily history, scene findings, medical history, medi-
cal records, prescription records, or information
from a prescription drug monitoring program).
This investigative information is then used in
conjunction with the results of the autopsy and
toxicological testing to determine a manner of
Davis et al. • Page 71
 death, whether accident, suicide, or homicide. preferable to general statements, avoid the use of
The determination of suicide is often difficult; personal identifiers in this section, as well as in
ME/Cs must base a determination of suicide on the cause of death section, because such informa-
REVIEW ARTICLE

appropriate investigative information and post-
mortem findings and be able to defend this de-
termination. Published guidelines from the CDC
indicate that in a suicide, the fatal injury must be
consistent with being self-inflicted and that there
should be indication of intent of self-harm (60-
62). By these criteria, intentional misuse of opi-
oids in excess amounts for self-treatment or for
the sensations that the drugs cause, while dan-
gerous, does not by itself constitute a suicide. At
the same time, assigning “undetermined” as the
manner of death as a matter of course for deaths
due to intoxication does not serve the public
good, nor does this practice support efforts to in-
tervene and prevent future intoxication deaths of
a similar sort. The panel recommends classify-
ing deaths from the misuse or abuse of opioids
without any apparent intent of self-harm as “ac-
cident.” Reserve “undetermined” as the manner
for the rare cases in which evidence exists to sup-
port more than one possible determination, that
is, where some evidence suggests accident and
other evidence suggests suicide or homicide.
How Injury Occurred
The drugs to which fatal intoxication is attributed
should be listed in the “Cause of Death” field.
The “How Injury Occurred” field should include
the known information about the history, route of
administration, drug source, and the type of drug
formulation (Table 4). Examples for “How Inju-
ry Occurred” might include: “history of chronic
back pain, ingested drug prescribed to decedent”
or “injected illicit substance.” The same cause
of death, “acute methadone intoxication,” could
occur under different circumstances. Death from
appropriate utilization of prescribed methadone
differs from death from inappropriate use of pre-
scribed methadone, which in turn differs from
illicit use of methadone, and each of these cir-
cumstances calls for a different public health re-
sponse to try to prevent such deaths in the future.
While it is true that more specific information is
tion may impede attempts to create de-identified
data for public health work and may later prove
to be incorrect.
SUMMARY
The recommendations of this panel are based
on the best evidence provided in the medical
literature for the investigation, evaluation, and
certification of opioid-related deaths at the time
of review. The panel recognizes that the foren-
sic science concerning postmortem toxicologi-
cal findings and interpretation lags behind the
mounting number of deaths from drug intoxica-
tion. Historically, case reports and case series
have provided the preponderance of evidence
concerning postmortem toxicology in humans.
Though each drug intoxication death is unique,
common patterns can be found when analytic
studies that investigate multiple factors and in-
volve large number of cases are employed. The
lack of studies serves as a call to forensic pa-
thologists and toxicologists to conduct research
to provide more refined evidence upon which to
base our practices. Large analytical studies can
advance forensic science further and more quick-
ly than continued dependence upon case series
and case reports, but this will require recognition
of pertinent cases on a large scale.
While ME/Cs and toxicologists value their abili-
ty to work independently, the recommended stan-
dard procedures strengthen the public health and
public safety community’s response to the opioid
epidemic and enhance the value of ME/C work
products. Use of these recommendations will im-
prove the detection and reporting of opioid-relat-
ed deaths resulting in more accurate benchmarks
by which to gauge the success of public health
and safety interventions.

Table 4: Useful Information for “How Injury Occurred”

Information Examples of Details

Medical history History of chronic pain, origin of pain (e.g., motor vehicle accident, fall, cancer), history or
evidence of drug use, abuse or misuse (e.g., intravenous abuse, prescription medication abuse,
methadone treatment, detoxification admissions)

Route of administration Oral ingestion, intravenous injection, snorted, smoked, transdermal, transmucosal, unknown

Source of drug Prescription, illicit street purchase, diverted from another person’s prescription, unknown source
Page 72 • Volume 3 Issue 1

Type of formulation Long-acting or extended release opioid, immediate-release opioid

APPENDIX opioids? (e.g., metabolites, postmortem redis-
tribution, presence of multiple drugs)
Note: searches formulated based on original
questions ((((“Mortality”[Mesh] OR “mortality”
[Subheading]) OR “Cause of Death”[Mesh]) OR
PubMed Search Strategies “Death”[Mesh]) AND (((“Analgesics, Opioid”
[Majr] OR “Analgesics, Opioid”[Pharmaco-

OPIOID DEATH TECHNICAL REPORT

Question 1: Within the bounds of state law, logical Action]) OR “Opiate Alkaloids”[Majr])
which deaths require assumption of jurisdic- OR “Opioid-Related Disorders”[Majr] AND
tion and performance of an autopsy? ((“1997/01/01”[PDAT] : “2012/12/31”[PDAT])
AND “humans”[MeSH Terms] AND English
(((“Mortality”[Mesh] OR “mortality”[Subheading]) [lang]))) AND (((((“Cadaver”[Mesh] OR
OR “Cause of Death”[Mesh]) OR “Death” “Autopsy”[Mesh]) OR “Postmortem Changes”
[Mesh]) AND (“Coroners and Medical [Mesh]) OR “Forensic Sciences/methods”[Mesh])
Examiners”[Mesh] OR (jurisdiction[All Fields] OR “Tissue Distribution”[Mesh]) OR “Toxicol-
OR jurisdiction/instrument[All Fields] OR ogy/methods”[Mesh])
jurisdiction’[All Fields] OR jurisdiction’s[All
Fields] OR jurisdictional[All Fields] OR Question 6: What should be the standards for
jurisdictionally[All Fields] OR jurisdictions[All determining and recording (certifying) cause
Fields] OR jurisdictions’[All Fields] OR of death, manner of death, and how injury oc-
jurisdictive[All Fields] OR jurisdictory[All curred (including wording on the death cer-
Fields])) AND (((“Analgesics, Opioid”[Majr] tificate)?
OR “Analgesics, Opioid”[Pharmacological Ac-
tion]) OR “Opiate Alkaloids”[Majr]) OR “Opi- ((“death certificates”[MeSH Terms] OR
oid-Related Disorders”[Majr]) (“death”[All Fields] AND “certificates”[All
Fields]) OR “death certificates”[All Fields]
Question 2: What constitutes appropriate and OR (“death”[All Fields] AND “certificate”[All
necessary scene investigation? (photographs, Fields]) OR “death certificate”[All Fields])
counting pills) AND English[lang]) AND ((“Analgesics,
Opioid”[Majr] OR “Opiate Alkaloids”[Majr])
(((“Analgesics, Opioid”[Majr] OR “Analgesics, OR “Opioid-Related Disorders”[Majr] AND
Opioid”[Pharmacological Action]) OR “Opiate English[lang])
Alkaloids”[Majr]) OR “Opioid-Related Disorders”
[Majr]AND ((“1997/01/01”[PDAT] : “2012/12/31” AUTHORS
[PDAT]) AND “humans”[MeSH Terms] AND
English[lang])) AND (((“Mortality”[Mesh] Lead Author:
OR “mortality”[Subheading]) OR “Cause of Gregory G. Davis MD MSPH
Death”[Mesh]) OR “Death”[Mesh]) AND
scene[All Fields] Opioid Panel:
Lewis S. Nelson MD – Chair
Question 3: When is it appropriate or nec- Sally S. Aiken MD
essary to perform toxicology testing? (e.g., Gregory G. Davis MD MSPH
screening bedside assay, based on scene) Henrik Druid MD PhD
James R. Gill MD
((“Analgesics, Opioid”[Majr] OR “Opi- Bruce A. Goldberger PhD
ate Alkaloids”[Majr]) OR “Opioid-Related Judy Melinek MD
Disorders”[Majr] AND ((“1992/01/01”[PDAT] Robert A. Middleberg PhD
: “2012/12/31”[PDAT]) AND “humans”[MeSH Owen L. Middleton MD
Terms] AND English[lang])) AND Jeanmarie Perrone MD
(“Toxicology”[Mesh] AND ((“1992/01/01” Paul M. Wax MD
[PDAT] : “2012/12/31”[PDAT]) AND Kurt B. Nolte MD – Principal Investigator
“humans”[MeSH Terms] AND English[lang]))
Review Consultants:
Questions 4 & 5: What represents appropriate Edward W. Boyer PhD MD
preanalytical issues (history, circumstances, Gregory J. Davis MD
anything about the body that would influence Corinne L. Fligner MD
testing), specimens, and toxicologic testing for Chris Gharibo MD
potential opioid related deaths. How does the Stacey Hail MD
interpretation of tissue drug concentrations Daliah Heller PhD MPH
impact the certification of deaths related to Jacqueline Martin MD
Davis et al. • Page 73
 Denise Paone EdD BSN
Agnieszka Rogalska MD
REVIEW ARTICLE
Information Management Consultant:
Gale G. Hannigan PhD MPH
ACKNOWLEDGEMENTS
The panelists gratefully acknowledge the tech-
nical support and expertise that librarians Gale
Hannigan and Brian Bunnett of the University of
New Mexico Health Sciences Library provided
by searching the literature, gathering articles,
checking citations and recording the outcome of
the review process. In addition, the panelists are
thankful for the assistance of Denise McNally of
the National Association of Medical Examiners
for facilitating the multiple conference calls re-
quired to produce the final document.
DISCLOSURES
Funding support for this project was received from
the Centers for Disease Control and Prevention
(CDC), contract number 00HCUD3-2011-99784.
The findings and conclusions in this report are
those of the authors and do not necessarily rep-
resent the official position of the CDC. Drs Ai-
ken, Greg G. Davis, Gill, Goldberger, Melinek,
Middleberg, Middleton, Nelson, Perrone and Wax
received travel funds from the CDC award to par-
ticipate in the expert panels. Drs. Goldberger and
Middleberg received honoraria for their participa-
tion in the expert panel. Drs Boyer, Gill, Melinek,
Nelson and Goldberger have received fees to be
expert consultants and provide testimony in le-
gal matters. Drs Gharibo and Gill have received
payments for lectures. Dr. Gill has received royal-
ties from the publication of scientific books and
the development of a Medicolegal course. Dr.
Middleberg is employed by the NMS laboratory
which has done fee-for-service work for the CDC.
Dr. Nolte’s institution, the New Mexico Office of
the Medical Investigator, received funds from the
CDC to support the creation of this paper includ-
ing his role as principal investigator and receives
funds from the National Association of Medical
Examiners (NAME) to support his role as Execu-
tive Vice President. In addition, Dr. Nolte’s institu-
tion has research awards in which he participates
from the National Institute of Justice and National
Institutes of Health (through Portland State Uni-
versity). Dr. Wax receives funds from the Ameri-
can College of Medical Toxicologists to be the
Executive Director.
The editors and publication staff do not report any
relevant conflicts of interest.
Page 74 • Volume 3 Issue 1
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