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**Acknowledgements**

Numerous people contributed to the development of the National
Assessment Meeting and this report (see Appendix A). The meeting was
conducted by Northrop Grumman Information Technology, Health Solutions &
Services, under contract 280-99-0900 with the Substance Abuse and Mental
Health Services Administration (SAMHSA), Center for Substance Abuse
Treatment (CSAT). Stewart B. Leavitt, PhD, served as researcher/writer
and Alan Trachtenberg, MD, MPH, was SAMHSA's medical editor and a
meeting facilitator. Johnson, Bassin & Shaw, Inc., provided assistance
in the production of this document. Raymond Hylton, Jr., RN, MSN, CSAT,
served as the Government project officer.

**Disclaimer**

The views, opinions and content of this publication are those of the
National Assessment participants, authors, and other referenced sources,
and do not necessar­ily reflect the views, opinions, or policies of CSAT,
SAMHSA, or any other part of the U.S. Department of Health and Human
Services (DHHS).

**Public Domain Notice**

Material appearing in this document -- except quoted passages, tables,
graphs, or figures from copyrighted sources -- is in the public domain
and may be repro­duced or copied without permission from SAMHSA or the
authors. Citation of the source is appreciated. However, this
publication may not be reproduced or distributed *for a fee* without the
specific, written authorization of the Office of Communications, SAMHSA,
DHHS.

**Electronic Access and Copies of Publication**

This publication may be accessed electronically through the following
Internet World Wide Web connection: [www.samhsa.gov]{.underline}. For
additional free copies of this document please call SAMHSA's National
Clearinghouse for Alcohol and Drug Information at 1‑800‑729‑6686 or
1‑800‑487‑4889 (TDD).

**Recommended Citation**

Center for Substance Abuse Treatment, Methadone-Associated Mortality:
Report of a National Assessment, May 8-9, 2003. CSAT Publication No.
28-03. Rockville, MD: Center for Substance Abuse Treatment, Substance
Abuse and Mental Health Services Administration, 2004.

**Originating Office**

Division of Pharmacologic Therapies, Center for Substance Abuse
Treatment, SAMHSA, DHHS, 5600 Fishers Lane, Rockville, MD 20857.

CSAT Publication No. 28-03

Printed 2004

# Preface

Methadone is a medication valued for its effectiveness in reducing the
mortality associated with opioid addiction as well as the various
medical and behavioral morbidities associated with addictive disorders.
It also is an inexpensive and increasingly popular analgesic medication
suitable for the treatment of even the most severe acute or chronic pain
in well-selected patients.

In 2002 and 2003, articles appeared in prominent newspapers -- including
the *New York Times* -- describing methadone as "widely abused and
dangerous." These alarming reports arose from an apparent increase in
deaths among persons using the medication.

The reports were of grave concern to the Substance Abuse and Mental
Health Services Administration (SAMHSA), the agency of the Department of
Health and Human Services which in 2001 assumed from the Food and Drug
Administration (FDA) the responsibility for regulation and oversight of
the Nation's opioid treatment programs (OTPs, commonly known as
methadone clinics). SAMHSA's Center for Substance Abuse Treatment (CSAT)
already was working with the Centers for Disease Control and Prevention
(CDC), the Drug Enforcement Administration (DEA), the National Institute
on Drug Abuse (NIDA), and the FDA, as well as with some of the States
most directly affected by rising methadone mortality rates. The media
reports, coupled with an increase in requests for consultation and
assistance from State authorities and practitioners in the field,
created added urgency for SAMHSA to evaluate and address the causes of
the increase.

To address these issues, SAMHSA convened a multidisciplinary group --
including representatives from various Federal and State agencies,
researchers, epidemiologists, pathologists, toxicologists, medical
examiners, coroners, pain management specialists, addiction medicine
experts, and others -- to conduct a National Assessment of
Methadone-Associated Mortality in May 2003.

The term "methadone-associated mortality" broadly encompasses fatalities
in which methadone has been detected during postmortem analysis or is
otherwise implicated in a death. Defining methadone's role in such
deaths is an unsettled area, complicated by inconsistencies in methods
of determining and reporting causes of death, the presence of other
central nervous system (CNS) drugs, and the absence of information about
the decedent's antemortem physical or mental condition and level of
opioid tolerance. Moreover, the source, formulation, and quantity of
methadone implicated in an individual's death often are difficult to
determine.

Participants in the National Assessment presented and carefully reviewed
the available data on methadone formulation, distribution, patterns of
prescribing and dispensing, as well as the relevant data on drug
toxicology and drug-associated morbidity and mortality. As a result of
their deliberations, participants arrived at a number of important
conclusions regarding the reports of methadone-associated mortality and
formulated recommendations for reducing that mortality.

This document summarizes the data used by the Assessment experts to
evaluate the nature and scope of the problem, as well as to present
their findings and recommendations. Participants' slides and other
presentation materials are available on SAMHSA's web site; a Background
Briefing Report prepared for the Assessment also is available on the web
site.

These documents provide an excellent source of information and expert
analysis of both anecdotal and statistical reports of
methadone-associated mortality. The conclusions of the experts assembled
for the National Assessment can help inform future policy and assure
that appropriate access to this important medication is preserved.

Charles G. Curie, MA, A.C.S.W., Administrator, Substance Abuse and
Mental Health Services Administration

H. Westley Clark, MD, JD, MPH, CAS, FASAM, Director, Center for
Substance Abuse Treatment, Substance Abuse and Mental Health Services
Administration

# Contents

(This document also is available in HTML format at
[www.samhsa.gov]{.underline}.)

Part 1. Purpose of the National Assessment

Part 2. Background

Methadone's Pharmacology and Mechanisms of Action

Methadone's Safety Profile

National Data on Methadone Use and Associated Mortality

State-Level Data on Methadone Use and Associated Mortality

Part 3. Deliberations

Part 4. Findings

Recent Increases in Methadone Use Are Related to Its Use as an Analgesic

Increases in Methadone-Associated Mortality Also Are Related to Its Use
as an Analgesic

OTPs and the Revised Federal Regulations Are Not Significant
Contributors to Methadone-Associated Mortality

Part 5. Recommendations

Uniform Case Definitions Should Be Established

Standards for Toxicologic Testing Are Needed

More Useful Data Are Needed

Health Professionals Need Better Training in Addressing Pain and
Addiction

Public Misperceptions About Methadone Must Be Addressed

Public Policies Must Respond to Multiple Needs

Part 6. Conclusions

Part 7. References and Bibliography

Part 8. Appendices

Appendix 1. Participants in the National Assessment

Appendix 2. Agenda

Appendix 3. Epidemiologic Databases Consulted

Appendix 4. Past Investigations of Methadone-Associated Mortality

Appendix 5. Methadone Serum Level Conversion Factors

Appendix 6. MedWatch Form

Appendix 7. PedTox Case Report Form (from NAME)

Appendix 8. Methadone Identified in Laboratory Testing

**Contents: Conference Papers**

(These documents, in HTML format, are available at
[www.samhsa.gov]{.underline}.)

**Background Briefing Report**

**Presentation Summaries and Speakers' Slides and Handouts**

**Part 1.** Introductory Remarks: Alan Trachtenberg, MD, MPH
(SAMHSA/CSAT)

**Part 2.** The Opioid Treatment Program (OTP) Perspective: Mark W.
Parrino, MPA, Meeting Co-Chair and President of The American Association
for the Treatment of Opioid Dependency (AATOD)

**Part 3.** Clinical Importance of Methadone in Opioid Agonist Therapy
(OAT) and Pain Management: Seddon Savage, MD, Meeting Co-Chair

**Part 4.** Challenges to Forensic Science: Bruce A. Goldberger, PhD,
DABFT, Meeting Co-Chair

**Part 5.** Drug Abuse Warning Network (DAWN) and Other SAMHSA Office of
Applied Studies Data: Elizabeth Crane, PhD, MPH (SAMHSA)

**Part 6.** Opioid Utilization Data: Automation of Reports and
Consolidated Order System (ARCOS): June E. Howard, Chief of the
Targeting and Analysis Unit in the Drug Operations Section, Office of
Diversion Control, Drug Enforcement Administration (DEA)

**Part 7.** Opioid Utilization Data: IMS Health: Laura Governale,
PharmD, Food and Drug Administration's (FDA) Office of Drug Safety,
Division of Surveillance, Research and Communication Support

**Part 8.** Methadone Mortality Data from MedWatch: Rita
Ouellete-Hellstrom, PhD, Martin Pollock, PharmD, and Lanh Green, PhD,
FDA Office of Drug Safety

**Part 9.** Surveillance of Medication-Related Mortality and Morbidity:
Dan Budnitz, MD, MPH, Centers for Disease Control and Prevention (CDC)
National Center for Prevention and Control

**Part 10.** Cardiac Questions: Mori J. Krantz, MD, Associate Professor
of Medicine and Cardiology, Denver Health

**Part 11.** New Population Based Data: Bridget Martell, MD, MA, Medical
Director, Melrose-on-Track Clinic, Albert Einstein College of Medicine

**Part 12.** Trends in Fatal Opioid Poisoning-National Numerator and
Death Certificate Data: Lois A. Fingerhut, MA, CDC's National Center for
Health Services

**Part 13.** State-Level Data: North Carolina: Catherine Sanford, MSPH,
Public Health Epidemiologist, North Carolina Department of Health and
Human Services

**Part 14.** State-Level Data: Maine: Marcella H. Sorg, PhD, RN,
University of Maine

**Part 15.** State-Level Data: Washington and Virginia: Ann Marie
Gordon, MS, State of Washington Toxicology Laboratory

**Part 16.** State-Level Data: Texas: Jane C. Maxwell, PhD, Gulf Coast
Addiction Technology Transfer Center, University of Texas at Austin

**Part 17.** National Violent Death Reporting System (NVDRS): Randy L.
Hanzlick, MD, Chief Medical Examiner for Fulton County, Georgia

**Part 18.** National Association of Medical Examiners (NAME) Pediatric
Toxicology Registry: John D. Howard, MD, Chief Medical Examiner for
Pierce County, Washington

**Part 19.** Consumer Product Safety Commission's Use of Death
Certificates: Tom Schroeder, MS, Consumer Product Safety Commission

**Part 20.** Electronic Prescription Monitoring Programs: Dana Droz, JD,
Kentucky

**Part 21.** Review of Methadone Related Deaths in Ontario: Douglas
Gourlay, MD, Anesthesiologist and Medical Consultant, Toronto, Ontario

# Part 1. Purpose of the National Assessment

Methadone has a long, successful history as a potent analgesic and a
highly effective medication for reducing the morbidity and mortality
associated with opioid addiction (Joseph and Woods, 1994; Joseph, et
al., 2000). However, recent reports of methadone-associated deaths have
stirred public concern. Diversion, abuse, and deaths associated with
many opioid medications, including methadone, have been the subject of
front-page news. Articles appearing in prominent newspapers, including
the *New York Times*, have described methadone as a "killer drug" that
is "widely abused and dangerous" (Belluck, 2003a, 2003b, 2003c;
Associated Press, 2002; *Washington Times*, 2003).

While these articles focused on the dangerous consequences of opioid
medications when misused, the articles often did not balance that
negative perspective with positive information about how the drugs
provide vital relief to persons suffering from serious pain and, in the
case of methadone, opioid addiction. The articles tended to perpetuate
long-standing myths and misconceptions about opioid-based medications.
Such misinformation has the potential to discourage the appropriate use
of these medications even though, properly administered, they have
demonstrated efficacy and safety in millions of patients worldwide.

The news reports were and remain of grave concern to the Substance Abuse
and Mental Health Services Administration (SAMHSA), within the U.S.
Department of Health and Human Services. In 2001, SAMHSA assumed
responsibility from the Food and Drug Administration (FDA) for the
regulation and oversight of the Nation's opioid treatment programs
(OTPs, commonly referred to as "methadone clinics"). SAMHSA's Center for
Substance Abuse Treatment (CSAT) already had been working with the
Centers for Disease Control and Prevention (CDC), the Drug Enforcement
Administration (DEA), the National Institute on Drug Abuse (NIDA), and
the FDA, as well as with some of the affected States, to assess the
issue of opioid overdose deaths. However, the media reports, combined
with increasing requests for consultation and assistance from State
authorities and practitioners in the field, added urgency to SAMHSA's
efforts to address the causes of methadone-associated mortality in a
focused and expeditious manner.

Thus, on May 8-9, 2003, SAMHSA's CSAT convened a multidisciplinary group
of more than 70 experts -- including representatives of various Federal
and State agencies, researchers, epidemiologists, pathologists,
toxicologists, medical examiners, coroners, pain management specialists,
addiction medicine experts, and others (see Appendix 1 for a complete
list of participants) -- to conduct a National Assessment of
Methadone-Associated Mortality.

The experts who participated in the National Assessment sought to
determine whether opioid treatment programs (OTPs) that use methadone in
the treatment of opioid addiction and the revised Federal regulations
governing the manner in which OTPs administer methadone could be
contributing to methadone-associated mortality.

Participants presented and carefully reviewed the available data on
methadone formulation, distribution, patterns of prescribing and
dispensing, as well as the relevant data on drug toxicology and
drug-associated morbidity and mortality. Based on their assessments,
participants arrived at a number of important conclusions regarding the
reports of methadone-associated mortality and formulated recommendations
for reducing that mortality.

# Part 2. Background

Methadone has a number of unique pharmacologic properties, such as its
slow onset and long duration of action, its relatively low need for dose
escalation because of tolerance, its antagonism of the glutamate
receptor N-methyl-D-aspartate (NMDA), its inhibition of
serotonin/norepinephrine reuptake, and its very modest cost -- all of
which make it an appropriate choice for opioid therapy of pain and
addiction (Savage, meeting presentation, 2003 \[see
[www.samhsa.gov]{.underline}\]; Lobert, 2003; Bruera, 2002; Payte, et
al., 1994; Joseph and Woods, 1994; Kreek, 1992; Ettinger, et al., 1979).

Methadone's Pharmacology and Mechanisms of Action

A synthetic opioid, methadone is among the most thoroughly studied drugs
in modern medicine. Approved by the FDA in 1947 as an analgesic, by 1950
methadone was being used to treat the painful symptoms of withdrawal
from heroin and other opioids. In 1964, researchers discovered that
continuous, daily maintenance doses of oral methadone allowed
opioid-addicted patients to function more normally in recovery (Payte,
1991; Zweben and Payte, 1990; Dole, 1988; Gearing and Schweitzer, 1974).

Oral methadone, whether used for addiction treatment or pain relief, is
available as a solid tablet, a rapidly dissolving wafer (diskette), and
a premixed liquid, all of which are essentially bioequivalent
(Mallinckrodt, 1995, 2000; Roxane, 1995, 1998, 2000). Each of the
formulations is 80 to 95 percent bioavailable (compared with only 30
percent for oral morphine) and readily absorbed (Eap, et al., 2000;
Inturrisi, 1972b).

Methadone is stored extensively in the liver and secondarily in other
body tissues. Its elimination half-life averages 24 to 36 hours at
steady state, but may range from 4 to 91 hours. Because of this long
half-life, achieving steady-state serum methadone levels (SMLs) -- in
which drug elimination is in balance with the amount of drug remaining
in the body -- requires, on average, from 4 to 5 days, although it can
take much longer in some individuals. When methadone is initiated,
before a steady state is achieved, a rule of thumb is that half of each
day's dose remains in the body to be added to the next day's new dose,
producing rising SMLs (which can reach dangerous levels if doses are
excessive). After each dose, the SML typically reaches a peak in 3 to 4
hours (with a range of 1 to 5 hours), although individual physiologic
responses differ for a variety of reasons (Eap, et al., 2002, 1988).

Largely as a function of liver enzyme activity, methadone is broken down
to form a number of inactive metabolites (Foster, et al., 1999; Kreek,
et al., 1979). Drugs that *induce* activity of these enzymes can
accelerate methadone metabolism, abbreviate the duration of its effects,
lower the SML, and precipitate abstinence (withdrawal) syndrome.
Conversely, drugs that *inhibit* these enzymes can slow methadone
metabolism, raise the SML, and extend the duration of drug effects (Eap,
et al., 1999). When interactions with other substances occur, changes in
SMLs can result in under- or over-medication. Genetic and environmental
factors also act on the enzymes, leading to considerable individual
variation in methadone potency (Nakamura, et al., 1982; Robinson and
Williams, 1971). Equally important to this kinetic variability, however,
is the wide inter-individual and intra-individual variation in opioid
tolerance, which is highly dependent on dosing history and even can
reflect external stimuli and environment (Eap, et al., 2002, 1988).

Methadone's Safety Profile

Through many years of clinical trials and experience, methadone has been
shown to have a favorable safety profile when used as indicated (Stine,
et al., 1998; Payte and Zweben, 1988; Zweben and Payte, 1990). Few
serious adverse reactions and no cumulative organ damage have been
associated with daily administration of appropriate doses over more than
20 years in some patients. Mortality from all causes is many-fold lower
in methadone-treated patients than in untreated opioid addicts. Studies
consistently have shown that the risk of communicable diseases (such as
HIV and hepatitis C) is significantly reduced by participation in
methadone maintenance therapy, even in patients who do not achieve total
abstinence from illicit drug use (Appel, et al., 2000; Backmund, et al.,
2001; Bell and Zador, 2000). Moreover, research shows that patients in
whom methadone therapy is discontinued have mortality rates three to
four times higher than patients in whom methadone therapy is continued
(Goldstein and Herrera, 1995; Concool, et al., 1979; Gearing and
Schweitzer, 1974).

Still, methadone is a potent drug; fatal overdoses have been reported
over the years (Baden, 1970; Gardner, 1970; Clark, et al., 1995;
Drummer, et al., 1992). As with most other opioids, the primary toxic
effect of excessive methadone is respiratory depression and hypoxia,
sometimes accompanied by pulmonary edema and/or aspiration pneumonia
(White and Irvine, 1999; Harding-Pink, 1993). Among patients in
addiction treatment, the largest proportion of methadone-associated
deaths have occurred during the drug's induction phase, usually when (1)
treatment personnel overestimate a patient's degree of tolerance to
opioids, or (2) a patient uses opioids or other central nervous system
(CNS) depressant drugs in addition to the prescribed methadone (Karch
and Stephens, 2000; Caplehorn, 1998; Harding-Pink, 1991; Davoli, et al.,
1993). In fact, when deaths occur during later stages of treatment,
other drugs usually are detected at postmortem examination (Appel, et
al., 2000). In particular, researchers have called attention to the
"poison cocktail" resulting from the intake of multiple psychotropic
drugs (Borron, et al., 2001; Haberman, et al., 1995) such as alcohol,
benzodiazepines, and other opioids. When used alone, many of these
substances are relatively moderate respiratory depressants; however,
when combined with methadone, their additive or synergistic effects can
be lethal (Kramer, 2003; Payte and Zweben, 1998).

It is important to note that postmortem blood concentrations of
methadone do not appear to reliably distinguish between individuals who
have died from methadone toxicity and those in whom the presence of
methadone is purely coincidental (Drummer, 1997; Caplan, et al., 1983).
This poses challenges for efforts to achieve more accurate forensic
determinations of cause of death in such cases, and underscores the need
for appropriate case definitions, as well as for improved systems to
gather and classify premortem and other data for surveillance and
prevention purposes (Hanzlick, 1997; Baden, 1978).

National Data on Methadone Use and Associated Mortality

Data from MedWatch -- the FDA's Safety Information and Adverse Event
Reporting Program -- indicate that, from 1970 through 2002, 1,114 cases
of methadone-associated deaths in adults were reported. Critically, a
greater number of methadone-associated deaths were reported in 2001
alone than during the entire period from1990 through 1999; this number
doubled again in 2002 (Ouelette-Hellstrom, et al., meeting presentation,
2003).

Reports from U.S. poison control centers also show that the overall
number of opioid-related deaths has been on the rise, with many cases
involving oxycodone and hydrocodone (Budnitz, meeting presentation,
2003; Litovitz, et al., 2002; Fingerhut and Cox, 1998; Cone, et al.,
2003; Florida Department of Law Enforcement, 2002; Eastwood, 1998).
Similarly, data from the Drug Enforcement Administration (DEA) National
Forensic Laboratory System (NFLS) indicate that seizures by law
enforcement agencies of illicitly obtained opioid analgesics such as
hydrocodone and oxycodone have outpaced seizures of methadone;
nevertheless, methadone seizures have been increasing as well (Howard,
meeting presentation, 2003). Methadone tablet seizures increased 133
percent between 2001 and 2002; in contrast, seizures of liquid methadone
increased only 11 percent during the same period (Howard, meeting
presentation, 2003).

Recently, the availability of low-cost, high-purity heroin in some parts
of the U.S. has fostered increased rates of abuse, since such heroin can
be smoked or ingested intranasally by new users, eliminating the need
for injection and thus fostering experimentation (SAMHSA, 2001;
McCaffrey, 1999). In such cases, miscalculations of drug purity have led
to fatal overdoses. As a result, death rates among IV heroin users are
13 times greater than those for the population as a whole (Zickler,
2001; SAMHSA, 2002).

The abuse of opioids other than heroin also is of concern. According to
SAMHSA's 2001 National Household Survey on Drug Abuse, the number of new
non-medical users of prescription drugs has increased steadily since the
mid-1980s. The greatest part of this increase involves non-medical use
of opioid analgesics, which increased from 400,000 persons in the
mid-1980s to about 2 million in 2000 (Crane, meeting presentation, 2003;
SAMHSA, 2001). Data from SAMHSA's Drug Abuse Warning Network (DAWN)
indicate that, in 2002, heroin/morphine, cocaine, and alcohol in
combination with other drugs -- such as opioid analgesics or marijuana
-- were the substances most often mentioned in national data on
drug-related deaths reported through DAWN (SAMHSA, 2003).

From 1994 to 2001, DAWN recorded an increasing number of opioid
analgesic mentions in drug-related emergency department visits, with the
largest increases reported for oxycodone (352 percent), methadone (230
percent), and hydrocodone (131 percent). In 2001, "opioid dependence"
(presumed to involve addiction rather than solely physical dependence)
was the most frequently mentioned motive for abuse of opioid analgesics,
followed by "suicide attempts," "psychotropic effects" and "unknown" or
"other" motives (SAMHSA, 2003).

State-Level Data on Methadone Use and Associated Mortality

In 2002 and 2003, concerns were heightened by news reports of
methadone-associated deaths in Maine, Florida, and North Carolina -- all
States in which per capita distribution of methadone tablets through
pharmacies exceeds the national average (Associated Press, 2002;
Ballesteros, et al., 2003; Sanford, 2002; Sorg, 2002, Sorg and
Greenwald, 2002). These data suggest a correlation between increased
pharmacy distribution of methadone tablets for pain management and
increased problems with methadone, including methadone-associated
deaths.

In Maine, surveillance data depict an increase in methadone-associated
fatalities that roughly parallels the increase in all drug deaths
between 1997 and 2002 (Sorg, meeting presentation, 2003; Sorg, 2002).
Opioid analgesics -- most often heroin/morphine, oxycodone, and
methadone -- were present in 71 percent of the deaths reported in the
State and were identified as causative in 53 percent (Sorg and
Greenwald, 2002). The number of deaths in which methadone was detected
doubled between 1999 and 2000, leveled off in 2001, then increased again
in 2002 (Sorg, 2002). A high rate of mental illness and physical
disorders (such as heart, lung, and liver disease), along with
concomitant use of psychiatric medications and benzodiazepines, also
were found in decedents (Sorg and Greenwald, 2002).

In Florida, cases of methadone-associated mortality showed a large
increase from 2001 to 2002. Although in the first six months of 2002
most deaths (83 percent) were attributed to use of multiple drugs, the
number in which methadone was deemed to be causative roughly equaled
those in which it was merely "present" (FDLE, 2002).

In North Carolina, the number of deaths associated with methadone
increased five-fold from 1997 through May 2001, for a total of 198 cases
over that five-year period (Sanford, meeting presentation, 2003). When
the source of the methadone could be determined (in about half the
cases), physician prescription orders were identified in 75 percent,
with the rest obtained from non-medical sources (e.g., prescribed to a
relative/friend, obtained at a party, or "street purchase"). Only four
percent of the decedents were participating in addiction treatment at or
near the time of death, and OTPs were considered an unlikely source of
the methadone involved in the fatal cases (Ballesteros, et al., 2003;
Sanford, 2002). During the time period examined, the amount of methadone
dispensed through retail outlets (primarily pharmacies) in North
Carolina increased four-fold; the amount distributed through OTPs
increased only two and a half times (Sanford, meeting presentation,
2003; Sanford, 2002).

In Washington State, methadone-associated deaths during the period 1993
through 2002 roughly paralleled those associated with oxycodone and
hydrocodone (Figure 1). Concomitant use of multiple drugs was reported
in 92 percent of deaths involving methadone (Gordon, meeting
presentation, 2003).

Figure 1. Deaths Associated With Opioid Analgesics in Washington State

![](media/image2.png){width="4.189583333333333in"
height="2.334722222222222in"}

Source: Washington State data courtesy of Ann Marie Gordon, MS.

In Texas, which experienced an increase in methadone-associated
fatalities during the early 1990s (Barrett, et al., 1996), cases of
overdose involving persons being treated in OTPs actually declined
between 1999 and 2002 (Maxwell, meeting presentation, 2003). Over the
same period, the number of death certificates that included mention of
methadone increased three-fold. Thus, while overdose mortality was
declining among OTP patients, such fatalities were rising in the overall
population (Maxwell, meeting presentation, 2003).

In States that have collected, analyzed, and reported relevant data,
methadone-associated mortality appears to be increasing, although the
absolute number of cases remains a relatively modest portion of the
total number of drug-related deaths (SAMHSA, 2002). Methadone seldom is
reported as the sole cause of death. In those relatively rare cases, the
drug often was ingested accidentally. The majority of
methadone-associated deaths involved at least one other drug, often
another opioid or central nervous system depressant such as alcohol or a
benzodiazepine (Borron, et al., 2001; Haberman, et al., 1995).

# Part 3. Deliberations

As part of the National Assessment, SAMHSA commissioned a Background
Briefing Report containing research data and other information to help
establish a common understanding of the problem. This briefing report
was distributed to participants in advance of the May meeting and is
available on SAMHSA's web site
([www.samhsa.gov](http://www.samhsa.gov/)).

Opening the meeting, CSAT Director H. Westley Clark, MD, JD, MPH, CAS,
FASAM, reaffirmed SAMHSA's concerns about methadone-associated mortality
and the importance of a response to the problem. He noted that, if OTPs
or their clinical practices were responsible for any part of the
increase in methadone-associated mortality, SAMHSA, as the Federal
agency that regulates such programs, would work actively to rectify the
problem. If, on the other hand, OTPs were not a significant source of
methadone in overdose cases, that finding should be documented and
communicated widely.

Next, SAMHSA's Alan Trachtenberg, MD, MPH, described the policy context
surrounding reports of opioid-associated deaths, particularly fatalities
involving methadone. Dr. Trachtenberg defined the meeting's objectives
as:

-   Determining whether OTPs' use of methadone in the treatment of
    opioid addiction and the revised Federal regulations governing the
    manner in which OTPs administer methadone could be contributing to
    methadone-associated mortality;

-   Assessing the need for improved nationwide surveillance of
    opioid-associated deaths, particularly methadone-associated
    mortality;

-   Assessing the adequacy of case definitions used by coroners and
    medical examiners (MEs) in the attribution of opioids' specific role
    in drug-associated deaths; and

-   Recommending preventive measures for implementation by health care
    professionals and educators, regulators, and law enforcement
    agencies at all levels of government.

Dr. Trachtenberg's remarks were followed by participants' presentations
of the epidemiologic data; problems involved in surveillance;
definitions and patterns of opioid misuse, abuse and addiction; and case
definitions of methadone-related fatalities. (Summaries of the
presentations and slide handouts are found online at
[www.samhsa.gov](http://www.samhsa.gov/).)

Each day's presentations were followed by action planning sessions that
focused on specific questions. Based on their review of background
information, speaker presentations, and the action planning sessions,
meeting participants reached consensus on a set of findings and
recommendations.

# Part 4. Findings

Concern over methadone-associated mortality is not new. Extensive
surveillance data have documented such deaths ever since methadone's
introduction as an analgesic and its subsequent use in the treatment of
opioid addiction. This has occurred within the context of increased
abuse of all opioid drugs (Crane, meeting presentation, 2003; ONDCP,
2002; SAMHSA, 2001).

The current analysis has prompted a number of important findings,
described in the following pages.

Recent Increases in Methadone Use Are Related to Its Use as an Analgesic

The greatest incremental growth in methadone distribution in recent
years is associated with use of the drug as an analgesic and its
distribution through pharmacies rather than through OTPs (Governale,
meeting presentation, 2003; DEA, 2003) (Figure 2). However, the growth
in distribution of methadone through pharmacies has been overshadowed by
the increase in distribution of oxycodone and hydrocodone.

Figure 2. Percent Change in Distribution of Methadone and Three
Comparison Drugs, from Baseline Year 1998 through 2002

![](media/image3.png){width="3.895138888888889in"
height="2.6569444444444446in"}

> Source: Data from IMS Health, National Prescription Audit Plus,\
> courtesy of Laura A. Governale, PharmD.

By comparison, distribution of methadone through OTPs remained
relatively flat during the period measured (Howard, meeting
presentation, 2003) (Figure 3).

Figure 3. Distribution of Methadone through OTPs and Pharmacies,
Compared

![](media/image4.png){width="3.922222222222222in"
height="2.4131944444444446in"}

Source: Data derived from DEA ARCOS-2;\
methadone pharmacy 2000 data are an interpolated estimate.

Although use of all formulations of methadone has shown steady,
incremental growth over the past several years (Figure 4), the
distribution of tablets (most often used in pain management) and
diskettes has surpassed that of liquid formulations (most often used by
OTPs). For example, the rate of increase from 1999 to 2002 was far
greater for tablets (331 percent) than for either diskettes (147
percent) or liquids (175 percent). In 2002, about 55 percent of all
methadone distributed nationwide was in the form of tablets or diskettes
(Howard, meeting presentation, 2003).

Figure 4. Methadone Distribution, by Formulation, 1998 -- 2002\
(grams per 100,000 population)

![](media/image5.png){width="4.885416666666667in" height="2.4in"}

Source: Adapted from DEA ARCOS-2 data provided by June E. Howard.

In 2002, OTPs accounted for the largest amount of methadone products
purchased (68 percent), followed by pharmacies (29 percent). However,
whereas OTPs purchased 98 percent of all the methadone sold in liquid
form and 79 percent of all the methadone sold in diskette form in the
U.S., pharmacies accounted for *88 percent* of all purchases of the
tablet form (OTPs purchased only 1.75 percent of the tablets). Within
OTPs nationwide during 2002, 65 percent of methadone was distributed as
liquids, 26 percent as diskettes, and less than one percent as tablets
(Howard, meeting presentation, 2003).

Increases in Methadone-Associated Mortality\
Also Are Related to Its Use as an Analgesic

The greatest incremental growth in methadone distribution in recent
years is associated with use of the drug as an analgesic and its
distribution through pharmacies. In fact, distribution of solid
methadone formulations (tablets and diskettes), primarily through
pharmacies, has surpassed distribution of the liquid formulations that
are the mainstay of dispensing in OTPs. From 1998 through 2002, the
volume of methadone distributed through pharmacies increased five-fold,
whereas the volume distributed through OTPs increased only 1.5-fold. In
2002 alone, pharmacies accounted for 88 percent of all purchases of
methadone tablets (DEA, 2003). Data from the DEA's ARCOS system indicate
that the growth in methadone distribution overall has lagged far behind
the increases seen for other opioid analgesics, such as oxycodone and
hydrocodone products (DEA, 2003).

The DEA data are supported by independent information from IMS Health,
which tracks drug prescriptions and sales through selected channels of
distribution (Governale, meeting presentation, 2003). From 1998 to 2002,
the number of retail prescriptions filled each year for oxycodone,
hydrocodone, morphine, and methadone all increased. While fewer
prescriptions were written for methadone than for the other three
opioids, the number of prescriptions for methadone increased three-fold
between 1998 and 2003 (from 0.5 to 1.8 million prescriptions) -- a rate
of increase larger than that for the other three drugs. The number of
units of methadone in solid form distributed through retail channels
averaged a 38 percent annual increase, whereas comparatively minor
growth was seen for solid formulations distributed through OTP channels.

Taken together, the data confirm a correlation between increased
methadone distribution through pharmacy channels and the rise in
methadone-associated mortality. This supports the hypothesis that the
growing use of oral methadone, prescribed and dispensed for the
outpatient management of chronic pain, explains the dramatic increases
in methadone consumption and the growing availability of the drug for
diversion to abuse.

OTPs and the Revised Federal Regulations Are Not

Significant Contributors to Methadone-Associated Mortality

A major concern of the National Assessment participants was whether OTPs
and the revised SAMHSA regulations governing the manner in which OTPs
administer and dispense methadone have contributed to recent increases
in methadone-associated mortality. The SAMHSA regulations effective in
2001 (42 CFR Part 8) allow patients -- especially those who are
relatively advanced in the course of treatment -- to take home doses of
methadone on an increased number of days.

Examination of the data available to the National Assessment
participants indicates that OTPs and the 2001 regulatory changes *did
not* have a significant effect on rates of methadone-associated
mortality. As already noted, the upward trend in fatalities involving
methadone appeared prior to 2001 and, thus, preceded SAMHSA's regulatory
changes (Kallan, 1998). The trend in methadone-associated deaths
parallels death rates associated with other opioid agents (SAMHSA,
2003). In the cases in which the sources of methadone associated with
deaths could be traced, OTPs did not appear to be involved. Within OTPs,
patient deaths during the start-up (induction) phase -- the period of
highest risk for in-treatment mortality -- are rare due to Federal
regulations that impose specific requirements on the induction
("loading") dose, as well as improvements in patient care that resulted
from the SAMHSA requirement that OTPs must be accredited.

Further, the growth in the number of OTPs administering methadone and in
the number of persons receiving methadone treatment has been modest and
does not parallel the rate of increase in methadone-associated deaths.
Although the data remain incomplete, National Assessment participants
concurred that methadone tablets and/or diskettes that have become
available through channels *other than OTPs* are most likely the central
factor in recent increases in methadone-associated mortality.

# Part 5. Recommendations

Available databases and other evidence support many valid and important
observations. However, participants in the National Assessment also
recognized that certain information deficits will require further
consideration as efforts to assess and address methadone-associated
mortality move forward.

Uniform Case Definitions Should Be Established

Comparisons of data from various epidemiologic databases or studies of
methadone-associated mortality are difficult, because they often do not
employ common terminology or definitions (Kung, et al., 2001). It would
be helpful to develop uniform medical examiner/coroner case definitions
and reporting methods, as well as a data-collection system sufficiently
comprehensive and flexible to handle new problems as they arise.

Scientifically concise and universally accepted case definitions can
address the critical distinction between deaths *caused* by methadone
and deaths in which methadone is a contributing factor or merely
present.

Professional organizations need to agree on a uniform nomenclature that
clearly distinguishes between the expected consequences of physiologic
dependence and drug tolerance (which occur with many commonly used
opioid medications) and the phenomenon of addiction (which is a chronic,
relapsing, neurobiological disorder with behavioral manifestations).

Development of a central repository for opioid-related medical
examiner/coroner cases -- that is, a National Opioid Death Registry --
would facilitate the necessary data compilations and analyses. National
Assessment participants concluded that Federal support and involvement
would be needed to ensure that comprehensive toxicologic analyses are
conducted in all local jurisdictions and reported to such a national
registry.

Standards for Toxicologic Testing Are Needed

Standards should be developed to guide toxicologic testing in cases of
suspected drug-induced deaths (Milroy and Forrest, 2000; Merrill, 1996;
Prouty and Anderson, 1990). National Assessment participants suggested
that the Food and Drug Administration might provide reference standards
for such toxicologic tests, with relevant professional organizations
providing input and assistance. Once standard case definitions are
determined, investigative techniques for medical examiners and coroners
should be enhanced and standardized.

More Useful Data Are Needed

Overall, more flexibility is needed in the design of data sets and the
performance of data analyses, as are better methods of integrating data
from different collection systems. Procedures for accessing new and
existing data also should be simplified.

Better information is needed to describe how methadone-associated deaths
occur. For example, data could inform whether the drug's potential for
lethality may be the result of a slow onset of action, leading to
repeated dosing -- and, ultimately, overdose -- as an individual
attempts to achieve the desired drug effect. Today, such a conclusion
requires additional information.

More information is needed about the particular formulations of
methadone -- tablets, diskettes, liquids, or injectables -- involved in
specific cases of mortality (natural, accidental, suicide, homicide, or
undetermined).

Accurate information is needed to determine the sources of methadone
associated with fatalities (e.g., thefts, robberies or diversion from
medical practices, pharmacies, or OTP clinics). For example, current
data indicate that most methadone-associated deaths, where dosage form
information is available, involve 5 and 10 mg tablets. However, it is
not clear whether those tablets are obtained through legal
prescriptions, prescription forgeries, other diversion tactics, or
pharmacy thefts or robberies. Future reviews will benefit from
improvements to DEA's Drug Theft System over the past year. These
changes will permit the extraction and review of data for specific drugs
in a more reliable manner. While more timely information will be
available, some limitations will remain, since the accuracy of the
system is totally dependent on pharmacies and other registrants
submitting acceptable reports. In addition, unlike other DEA systems,
the Drug Theft System is not completely automated and relies instead on
the manual inputting of data.

More information is needed about the population being legitimately
prescribed methadone -- their health history, concomitant use of other
medications, and current or past involvement with alcohol or other
drugs. This information would be useful in assessing factors that may be
contributing to mortality and why so many fatalities involve individuals
using multiple drugs.

It would be helpful to know what information individuals are receiving
from their physicians when methadone is prescribed, and whether patients
and prescribers fully understand the potential dangers of methadone
misuse and abuse.

It also would be useful to compare data from IMS Health, ARCOS, or State
prescription monitoring programs (PMPs) with medical examiner data to
estimate how much methadone is being prescribed in regions that report
increased cases of methadone-associated deaths. The group endorsed the
expansion of PMPs, including creation of a uniform system for reporting
and compiling data, leading to a national database. However,
participants also recognized that PMPs have limitations and need to be
improved, and that further assessment of possible adverse effects on
patient confidentiality and access to care is needed (Droz, meeting
presentation, 2003).

Better information is needed about the nature of education and
prevention messages currently being communicated to and by the public,
patients, practitioners, and the media. Given inaccurate or incomplete
information, patients may be deterred from seeking treatment using
methadone or other opioid drugs for legitimate medical problems,
including addiction. Anecdotal information contributed by meeting
participants suggests an urgent need to clarify popular misperceptions
and to correct misinformation at all levels.

In identifying data needs, participants concluded that it would be
helpful to know of any specific national and local concerns. Whatever
research occurs should be interdisciplinary, involving stakeholders from
various fields. It would be helpful if the Federal government developed
a special work group to focus on this issue.

Health Professionals Need Better Training in Addressing Pain and
Addiction

Today, pain and addiction are recognized as pervasive medical disorders
for which health professionals have an ethical obligation to provide the
best available treatment. All FDA-approved opioid medications, including
methadone, are powerful and useful drugs in this treatment. On the other
hand, inappropriate prescribing, misuse, and abuse of prescription
opioids (including methadone) are serious public health problems
attended by substantial morbidity and mortality. The medical community
and government agencies are responsible both for ensuring that such
medications continue to be available for therapeutic use and for
preventing their misuse or abuse.

Thus, physicians and other health professionals must become
well-grounded in their knowledge of how to treat both pain and
addiction. Accordingly, the diagnosis and treatment of addiction, and
appropriate pharmacotherapies for pain and addiction, should be part of
core educational curricula for all health care professionals. In
particular, physicians need to understand methadone's pharmacology and
appropriate use, as well as specific indications and cautions to
consider when deciding whether to use this medication in the treatment
of pain or addiction. While this recommendation is relevant to the
educational needs of the medical community as a whole, it has particular
resonance for staff of OTPs and physicians who provide pain treatment.

Public Misperceptions About Methadone Must Be Addressed

There is an immediate need for professional organizations and regulatory
agencies to present scientific evidence and credible data to counter
misinformation about methadone and "methadone clinics" (OTPs) presented
in the mass media. The public needs to know that methadone-associated
mortality is being addressed, and that when methadone is prescribed,
dispensed, and used appropriately, related mortality is virtually
eliminated. To this end, National Assessment participants agreed that
professional associations, provider organizations, and advocacy groups
need to be engaged in these educational activities.

Participants also agreed that a special evidence-based "White Paper" on
methadone should be developed to communicate vital information to
policymakers, health professionals, and the public. Such a White Paper
would incorporate information from the meeting deliberations and
Background Briefing Report prepared for the National Assessment, in
addition to other information that may be required to address a range of
issues.

The contents of the White Paper could be made available in relevant form
to various stakeholder groups, including: addiction treatment providers
(physicians, nurses, counselors) and administrators, pain management
specialists, psychiatrists, pharmacists, and others. Patient advocacy
groups also could play a significant role in disseminating this vital
information.

National Assessment participants viewed the White Paper as an organizing
tool and as a way to initiate a process that could become more
far-reaching in its objectives.

Public Policies Must Respond to Multiple Needs

More than 50 years of clinical experience have shown that methadone is a
fundamentally safe and effective medication. Accordingly, neither policy
nor regulatory concerns should impede patients' access to medically
indicated use of methadone and other medications vital to the treatment
of pain and addiction.

Any comprehensive framework affecting health care policy and medical
practice regarding opioid medications should address the needs of law
enforcement and regulatory agencies, professional education, pain
management, and addiction treatment providers. For example, National
Assessment participants agreed that broad regulatory actions directed
toward all OTPs, such as State-imposed restrictions on prescribing
methadone, are unlikely to be effective. The exception would be actions
focusing on particular programs or geographic areas where problems are
identified. In the absence of such specific problems, generalized
actions against OTPs would have no effect on the overall mortality
problem at best and, at worst, could have damaging effects on the
availability of a vital treatment modality.

# Part 6. Conclusions

From the data examined during this National Assessment, it appears that
the recent upsurge in public concern over methadone abuse and fatalities
is linked to several factors, some of which may be an appropriate
impetus to new health policy.

-   **First**, recent years have seen documented increases in abuse of
    heroin and all opioid analgesics. When their preferred drugs are not
    available, some individuals turn to abuse of methadone.

-   **Second**, over the same period, methadone (primarily in tablet
    form) has become more accessible as physicians increasingly have
    prescribed it for pain relief.

-   **Third**, press reports in some States have suggested that
    methadone has become more available to unauthorized users following
    the adoption of new Federal regulations that enabled OTPs to relax
    their policies regarding take-home doses of methadone. However,
    these allegations are not supported by the data reviewed during the
    National Assessment. In fact, the perception that OTPs are
    contributing to the problem of overdose deaths appears to be highly
    exaggerated. An argument can be made that Federal requirements for
    dosing during the start-up (induction) phase of methadone
    maintenance treatment actually may have helped to minimize
    methadone-associated fatalities. It also should be noted that OTPs
    provide demonstrably effective treatment for opioid addiction.

Three primary scenarios characterize current reports of
methadone-associated mortality:

1.  In the context of legitimate patient care, methadone accumulates to
    harmful serum levels during the first few days of treatment for
    addiction or pain (that is, the induction period before methadone
    steady state is achieved or tolerance develops).

2.  Illicitly obtained methadone is used by some individuals who have
    diminished or no tolerance to opioids and who may use excessive
    and/or repetitive doses in an attempt to achieve euphoric effects.

3.  Methadone -- either licitly administered or illicitly obtained -- is
    used in combination with other CNS depressant agents (such as
    benzodiazepines, alcohol, or other opioids).

The data reviewed for this National Assessment show that the greatest
incremental growth in methadone distribution in recent years is
associated with use of the drug as an analgesic and its distribution
through pharmacies. In fact, the rate of increase in distribution of
solid methadone formulations (tablets and diskettes), primarily through
pharmacies, has surpassed the rate of increase in distribution of the
liquid formulations that are the mainstay of dispensing in OTPs (Figure
5).

Figure 5. Number of Units of Methadone Distributed Through Retail and
Other Channels, by Dosage Form

![](media/image6.png){width="4.706944444444445in"
height="2.954861111111111in"}

> Data from IMS Health, Retail and Provider Perspective,\
> courtesy of Laura A. Governale, PharmD.

Taken together, the data confirm a correlation between increased
methadone distribution through pharmacy channels and the rise in
methadone-associated mortality. The data, thus, support the hypothesis
that the growing use of oral methadone, prescribed and dispensed for the
outpatient management of pain, explains the dramatic increases in
methadone consumption and the growing availability of the drug for
diversion to illicit use. Although the data remain incomplete, National
Assessment meeting participants concurred that methadone tablets and/or
diskettes distributed through channels *other than OTPs most likely are
the central factor in methadone-associated mortality*.

With the release of this National Assessment Report, it is hoped that
action will be initiated at the Federal and State levels, and in the
public and private sectors, to implement the recommendations offered
here. Additionally, SAMHSA must continue its current vigilance and
ongoing efforts to improve the quality, safety, efficacy, and
reliability of addiction treatment, as well as enhancing patient
satisfaction and community understanding and acceptance of methadone
treatment. This will ensure that OTPs continue to make an important
contribution to solving the problem of methadone-associated mortality.

# Part 7. References and Bibliography

Appel PW. Joseph H, Richman BL. Causes and rates of death among
methadone maintenance patients before and after the onset of the
HIV/AIDS epidemic. Mt Sinai J Med. **2000**;67(5-6):444-451.

Associated Press. Overdose increases linked to methadone. Stuart News
(Stuart, Florida). October 4, **2002**.

Backmund M, Meyer K, Von Zielonka M, Eichenlaub D. Treatment of
hepatitis C infection in injection drug users. Hepatology.
**2001**;34(1):188-193.

Backmund M, Meyer K, Zwehl W, Nagengast O, Eichenlaub D. Myocardial
infarction associated with methadone and/or dihydrocodeine. Eur Addict
Res. **2001a**;7(1):37-39.

Baden MM. Evaluation of deaths in methadone users. Leg Med Annu.
**1978**;127--31.

Baden MM. Methadone related deaths in New York City. Int J Addict.
**1970**;5(3):489-498.

Ballesteros MF, Budnitz DS, Sanford CP, Gilchrist J, Agyekum GA, Butts
J. Increase in deaths due to methadone in North Carolina \[research
letter\]. JAMA. **2003**;290(1):40.

Barrett DH, Luk AJ, Parrish RG, Jones TS. An investigation of medical
examiners cases in which methadone was detected, Harris County, Texas,
1987-1992. J Forensic Sci, JFSCA. **1996**;41(3):442-448.

Barton WI. Deaths involving methadone: A statistician's view. Drug
Forum. **1975**;4(2):139-158.

Bartu EE, Popescu A, Heutt KF, Hansson R, Plumley N. Methadone-related
deaths in Western Australia 1993-99. Aust NZ J Pub Health.
2002;26(4):364-370.

Bell J, Zador D. A risk-benefit analysis of methadone maintenance
treatment. Drug Saf. **2000**;22(3)179-190.

Belluck P. Methadone, once the way out, suddenly grows as killer drug.
New York Times (National Edition). New York Times. February 9,
**2003A**: 1,20.

Belluck P. Overdoses and deaths from abuse of drug methadone are up. New
York Times. February 2, **2003B**.

Belluck P. Recently for drug abusers, methadone has become a
double-edged sword. New York Times (National Edition). February 9,
**2003C**: 20.

Bendavid, N. Survey of drugs in Cook County: 333,000 labeled hard-core
users. Chicago Tribune. December 12, **1997**;sec 1:1.

Bittar P, Piguet V, Kondo-Oestreicher J, et al. Methadone induced long
QTc and "torsade de pointe." Swiss Medical Forum (Forum Med Suisse).
**2002**(Apr 10, Suppl 8):36S. \[Abstract P244.\]

Borron SW, Monier C, Risede P, Baud FJ. Interaction of opiates with
benzodiazepines in overdoses. J Toxicology:Clin Toxicology.
**2001**;39(3):212.

Bowler GM, Galloway DW, Meiklejohn BH, and Macintyre CC. Sharp fall in
blood pressure after injections of heparin containing chlorbutanol.
Lancet. **1986**;1:848-849.

Brown FM, Griffiths PS. P450 Guide: Comprehensive Enzymatic Drug
Metabolism Reference. 2nd ed. Montgomery, AL: P450Guide.com; **2000**.

Bruera E. Opioid rotation, methadone urged for hard-to-treat cancer
pain. Presentation at 14th international meeting of MASCC. In: Oncology
News International. **2002**;11(12):55.

Cairns A, Roberts IS, Benbow EW. Characteristics of fatal methadone
overdose in Manchester, 1985--94. BMJ. **1996**;313(7052):264--265.

Caplan YH, Ottinger WE, Crooks CR. Therapeutic and toxic drug
concentrations in post mortem blood: A six year study in the State of
Maryland. J Anal Toxicol. **1983**;7(5):225-230.

Caplehorn JRM. Deaths in the first two weeks of maintenance treatment in
NSW in 1994: Identifying cases of iatrogenic methadone toxicity. Drug
and Alcohol Review. **1998**;17:9-18.

Caplehorn JRM, Drummer OH. Mortality associated with New South Wales
methadone programs in 1994: Lives lost and saved. Med J Aust.
**1999**;170(3):104-109.

CDHAG (Commonwealth Department of Health and Aged Care). Induction and
Stabilisation of Patients Onto Methadone. Monograph Series No. 39.
Canberra: Commonwealth of Australia; **2000**. Available at
http://www.health.gov.au.

Chang A, Emmel DW, Rossi GC, Pasternak GW. Methadone analgesia in
morphine-insensitive CXBK mice. Eur J Pharm. **1988**;351:189-191.

Codd E, Shank R, Schupsky J, Raffia R. Serotonin and norepinephrine
uptake inhibiting activity of centrally acting analgesics: structural
determinants and role in antinociception. J Pharmacol Exp Ther.
**1995**;274:1263-1270.

Clark JC, Milroy CM, Forrest ARW. Deaths from methadone use. J Clin For
Med. **1995**;2:143-144.

COMPA (New York State Committee of Methadone Program Administrators).
Regarding Methadone Treatment and Other Pharmacotherapies: A Review. New
York, NY: COMPA; revised **1999**. See also: http:www.compa-ny.org.

Concool B, Smith H, Stimmel B. Mortality rates of persons entering
methadone maintenance: A seven--year study. Am J Drug Alcohol Abuse.
**1979**;6(3):345-353.

Cone EJ, Fant RV, Rohay JM. Oxycodone involvement in drug abuse deaths:
A DAWN-base classification scheme applied to an oxycodone postmortem
database containing over 1000 cases. J Analyt Tox. **2003**;27:57-67.

Cozza KL, Armstrong SC. The Cytochrome P450 System: Drug Interaction
Principles for Medical Practice. Washington, DC: American Psychiatric
Publishing, Inc.;**2001**.

D\'Aunno T, Pollack HA. Changes in methadone treatment practices:
Results from a national panel study, 1988-2000. JAMA. **2002** Aug
21;288(7):850-6.

Davis AM, Inturrisi CE. d-Methadone blocks morphine tolerance and
N-Methyl-D-Aspartate (NMDA)-induced hyperalgesia. J. Pharmacol Exp Ther.
**1999**;289:1048-1053.

Davoli M, Perucci CA, Forastiere F, et al. Risk factors for overdose
mortality: A case-control within a cohort of intravenous drug users. Int
J Epidemiol. **1993**;22(2):273--277.

Dole VP, Foldes F, Trigg H, et al. Methadone poisoning. NYS J Med.
**1971**;71:541-543.

Dole VP. Implications of methadone maintenance for theories of narcotic
addiction. JAMA. **1988**;260:3025-3029.

Dorsey JS. Serum methadone levels and optimal dosing in methadone
maintained patients. Poster presented at: American Association for the
Treatment of Opioid Dependence Conference; April 13-16, **2003**;
Washington, DC. Poster P9.

Drasch G, Quitterer D, Roider G, Von Meyer L. The enantioselective
detection of L- and D-methadone in blood samples from living and
deceased addicts \[German, abstract in English\]. Rechtsmedizin.
**2000**;10(5):170-175.

Drummer OH, Opeskin K, Syrjanen M, Cordner SM. Methadone toxicity
causing death in ten subjects starting on a methadone maintenance
program. Am J Forensic Med Pathol. **1992**;13(4):346--350.

Drummer OH, Syrjanen M, Opeskin K, Cordner SM. Deaths of heroin addicts
starting on a methadone maintenance programme. Lancet.
**1990**;335(8681):108.

Drummer OH. The toxicology of methadone and its involvement in sudden
death. In: 35th Annual TIAFT (The International Association of Forensic
Toxicologists) Conference. Padua, Italy; **1997**. Abstract 020.

Eap CB, Bourquin M, Martin J-L, et al. Plasma concentrations of the
enantiomers of methadone and therapeutic response in methadone
maintenance treatment. Dru Alcohol Dep. **2000**;6(11):47-54.

Eap CB, Buclin T, Baumann P. Interindividual variability of the clinical
pharmacokinetics of methadone: Implications for the treatment of opioid
dependence. Clin Pharmacokin. **2002**;41(14):1153-1193.

Eap CB, Déglon J-J, Baumann P. Pharmacokinetics and pharmacogenetics of
methadone: Clinical relevance. Heroin Add & Rel Clin Probl
**1999**;1(1):19-34.

Eap CB, Finkbeiner T, Gastpar M, Schebaum N, Bertschy G, Baumann P. High
inter-individual variability of methadone enantiomer blood levels to
dose ratios \[letter\]. Arch Gen Psychiatry **1988**;55:89-90.

Eastwood JA. Methadone poisoning in children. SOFT-TIAFT 1998 (Society
of Forensic Technologists-The International Association of Forensic
Toxicologists) Albuquerque, New Mexico; October 7, **1998**. Scientific
Session 1.

Editorial. Medicine or menace? The Washington Times. February 19,
**2003**.

Editorial. Methadone overdoses: Abuse of drug spreading so let's
restrict the amount. Portland Press Herald (Portland, Maine). September
18, **2002**.

Ehlers S. U.S. Congress ponders anti-methadone bill \[press release\].
Washington, DC: Drug Policy Foundation; February 19, **1999**.

English DR, Holman CDJ, Milne E, et al. The quantification of
drug-caused morbidity and mortality in Australia, 1995 edition.
Canberra: Commonwealth Department of Human Services and Health. AGPS.
**1995**:539-542.

Ettinger DS, Vitale PJ, Trump DL. Important clinical pharmacologic
considerations in the use of methadone in cancer patients. Cancer Treat
Rep. **1979**;63(3):457-459.

Federal Register. Narcotic drugs in maintenance and detoxification
treatment of narcotic dependence; Repeal of current regulations and
proposal to adopt new regulations. Federal Register. July 22,
**1999**;64(140):39809-39857. 21 CFR Part 291; 42 CFR Part 8. Available
from the Federal Register Online via GPO at: www.access.gpo.gov/su_docs.
Accessed August 1, 1999.

Federal Register. Opioid drugs in maintenance and detoxification
treatment of opiate addiction; Final rule. **2001** (Jan
17);66(11):4085. 42 CFR Part 8.

FDLE (Florida Department of Law Enforcement). 2002 Interim Report of
Drugs Identified in Deceased Persons by Florida Medical Examiners.
November **2002**. Available at:
http://www.fdle.state.fl.us/publications/examiner_drug_report_2002.pdf.

Fingerhut LA, Cox CS. Poisoning Mortality, 1985-1995. Pub Health Rep.
**1998**;113(3):218-233

Flanagan RJ, Rooney C. Recording acute poisoning deaths. Forensic Sci
Int. **2002**;128:3-19.

Foster DJR, Somogyi AA, Bochner F. Methadone N-demethylation in human
liver microsomes: lack of stereoselectivity and involvement of CYP3A4.
Br J Clin Pharmacol **1999**;47:403-412.

Frost JL. Commentary on: Oxycodone involvement in drug abuse deaths: A
DAWN-base classification scheme applied to an oxycodone postmortem
database containing over 1000 cases. J Analyt Tox. **2003**;27:67.

GAO (General Accounting Office). Methadone maintenance: some treatment
programs are not effective; greater Federal oversight needed. Report to
the chairman, Select Committee on Narcotics Abuse and Control, House of
Representatives. Washington, DC: U.S. General Accounting Office;
**1990**. Pub# GAO/HRD-90-104.

Gardner R, Methadone misuse and death by overdosage. Br J Addict.
**1970**; 65(2):113--118.

Gearing FR, Schweitzer MD. An epidemiologic evaluation of long--term
methadone maintenance treatment for heroin addiction. Am J Epidemiology.
**1974**;100:101--111.

Gfroerer J, Penne M, Pemberton M, Folsom R. Substance abuse treatment
need among older adults in 2020: The impact of the aging baby-boom
cohort. Drug Alcohol Depend. **2003**;69(2):127-135.

Glauser FL, Downie RL, Smith WR. Electrocardiographic abnormalities in
acute heroin overdosage. Bull Narc. **1977**;29(1):85-89.

Goldstein A, Herrera J. Heroin addicts and methadone treatment in
Albuquerque: a 22-year follow-up. Drug Alcohol Depend.
**1995**;40(2):139-150.

Gordon NB. The functional potential of the methadone maintained person.
CDRWG Monograph #2. Chemical Dependency Research Working Group: The New
York State Office of Alcoholism and Substance Abuse Services. December
**1994**:43-46.

Gorman AL, Elliott KJ, Inturrisi CE. The d- and l- isomers of methadone
bind to the non-competitive site on the N-methyl-D-aspartate (NMDA)
receptor in rat forebrain and spinal cord, Nerurosci Lett. **1997**;223:
5-8.

Gourevitch MN, Hartel D, Tenore P, et al. Three oral formulations of
methadone. A clinical and pharmacodynamic comparison. J Subst Abuse
Treat. **1999**;17(3):237-241.

Gottheil E, Sterling RC, Weinstein SP. Diminished illicit drug use as a
consequence of long-term methadone maintenance. J Addict Dis.
**1993**;12(4):45-57.

Green H, James RA, Gilbert JD, Harpas P, Byard RW. Methadone maintenance
programs -- A two-edged sword? Amer J For Med Path.
**2000**;21(4):359-361.

Greene MH, Luke JL, DuPont RL. Opiate overdose deaths in the District of
Columbia. II. Methadone-related fatalities. J Forensic Sci.
**1974**;19(3):575-584.

Greenfield L, Fountain D. Influence of time in treatment and follow-up
duration on methadone treatment outcomes. J Psychopath Behavioral
Assess. **2000**;22(4):353-364.

Haberman PW, Noble JA, DuFour MC. Alcohol use in combination with
cocaine, heroin, and methadone by medical examiner cases. J Stud
Alcohol. **1995**;56:344-347.

Hampton CT. Long QT syndrome: more common than you thought. Clin Rev.
**2003**;13(1):40-46.

Hanzlick R. Death registration: history, methods, and legal issues. J
Forensic Sci. **1997**;42(2):265-269.

Hanzlick R, Hunsacker III JC, Davis GJ. A Guide for Manner of Death
Classification. 1st Edition. St. Louis, MO: National Association of
Medical Examiners; February **2002**.

Harding-Pink, D. Deaths associated with methadone. J Toxicol Clin Exp.
**1991**;11(1):31-49.

Harding-Pink D. Opioid toxicity. Lancet. **1993**;341:665-666.

Heinemann A, Iwersen-Bergmann S, Stein S, Schmoldt A, Puschel K.
Methadone-related fatalities in Hamburg 1990-1999: Implications for
quality standards in maintenance treatment? Forensic Sci Int.
**2000**;113(1-3):449-455.

Heroin abuse and addiction. National Institutes on Drug Abuse (NIDA)
Research Report Series. **1997** (October). NIH Pub# 97-4165.

Horrigan FT. Methadone block of neuronal K current. Biophysical J.
**1990**;57:515A. Abstract W-Pos392.

Hser Y-I, Grella CE, Anglin MD. A 33-year follow-up of narcotics
addicts. Arch Gen Psychiatry. **2001**:58:503-508.

Huber A, Ling W, Fradis J, Charuvastra VC. Comparison of the effects of
methadone and LAAM on the electrocardiogram. Poster presented at:
College of Problems of Drug Dependence (CPDD) 63rd Annual Scientific
Meeting, Phoenix, AZ, June 20, **2001**. Also in: Huber A, Ling W,
Fradis J, Charavastra VC. Comparison of the effects of methadone and
LAAM on the electrocardiogram \[abstract\]. Drug Alcohol Depend.
2001;63:S70.

Huidobro F, Tamayo L, Contreras E. Effects of methadone on the action of
catecholamines in isolated preparations. Arch Int Pharmacodyn Ther.
**1971**;192:168-178.

Inturrisi CE, Verebely K. A gas-liquid chromatographic method for the
quantitative determination of methadone in human plasma and urine. J
Chrmatogr. **1972a**;65:361-369.

Inturrisi CE, Verebely K. The levels of methadone in the plasma in
methadone maintenance. Clin Pharm Ther. **1972b**;13(5 part 1):633-637.

Joseph H, Appel P. Historical perspectives and public health issues. In:
Parrino MW, chair. State Methadone Treatment Guidelines. Treatment
Improvement Protocol (TIP) Series 1. Rockville, MD: U.S. Department of
Health and Human Services; Center for Substance Abuse
Treatment;**1993**:11-24 DHHS Pub# (SMA) 93-1991.

Joseph H, Stancliff S, Langrod J. Methadone maintenance treatment (MMT):
A review of historical and clinical issues. Mt Sinai J Med.
**2000**;67(5-6):347-364.

Joseph H, Woods JS eds. Methadone Treatment Works: A Compendium for
Methadone Maintenance Treatment. CDRWG Monograph Series #2. Chemical
Dependency Research Working Group: The New York State Office of
Alcoholism and Substance Abuse Services. December **1994**. Available
at: http://users.rcn.com/nama.interport/mono2.htm. Accessed May 23,
2002.

Kallan JE. Drug abuse-related mortality in the United States: Patterns
and correlates. Amer J Drug Alcohol Abuse. **1998**;24(1):103-117.

Karch SB. Stephens BG. Toxicology and the pathology of deaths related to
methadone: Retrospective review. West J Med. **2000**;172:11-14.

Katchman AN, McGroary KA, Kilborn MJ, Kornick CA, Manfredi PL, Woosley
RL, Ebert SN. Influence of opioid agonists on cardiac human
*ether-a-go-go*-related gene K^+^ currents. J Pharm Exp Ther.
**2002**;303(3):688-694.

Kauffman JF, Woody GE. Matching Treatment to Patient Needs in Opioid
Substitution Therapy. Treatment Improvement Protocol (TIP) Series 20.
Rockville, MD: U.S. Department of Health and Human Services; Center for
Substance Abuse Treatment;**1995**. DHHS Pub# (SMA) 95-3049.

Kocheril AG, Bokhari SA, Batsford WP, Sinusas AJ. Long QTc and torsades
de pointes in human immunodeficiency virus disease. Pacing Clin
Electrophysiol. **1997**;20(11):2810-2816.

Kramer T. Side effects and therapeutic effects. Medsacape Gen Med.
**2003**;5(1). Available at http://www.medscape.com.

Krantz MJ, Lewkowiez L, Hays H, et al. Torsade de pointes associated
with very-high-dose methadone. Ann Intern Med. **2002**;137:501-504.

Kreek MJ. A personal retrospective and prospective viewpoint. In:
Parrino MW. State Methadone Treatment Guidelines. Treatment Improvement
Protocol (TIP) Series 1. Rockville, MD: U.S. Department of Health and
Human Services; Center for Substance Abuse Treatment;**1993**:133-143.
DHHS Pub# (SMA) 93-1991.

Kreek MJ, Gutjahr CL, Garfield JW, Bowen DV, Field FH. Drug interactions
with methadone. Ann NY Acad Sci. **1976**;281:350-370.

Kreek MJ, Hachey DL, Klein PD. Stereoselective disposition of methadone
in man. Life Sci. **1979**;24:925-932.

Kreek MJ. Medical safety and side effects of methadone in tolerant
individuals. JAMA. **1973a**;223:665-668.

Kreek MJ. Plasma and urine levels of methadone. NY State J Med.
**1973b**;73(23):2773-2777.

Kreek MJ. Rationale for maintenance pharmacotherapy of opiate
dependency. In: O'Brien CP, Jaffe JH. Addictive States. New York, NY:
Raven Press, Ltd.; **1992**:205-229.

Kringsholm B. Deaths among drug addicts in Denmark in 1968-1986.
Forensic Sci Int. **1988**;38(1--2):139-149.

Kringsholm B, Kaa E, Steentoft A, Worm K, Simonsen KW. Deaths among drug
addicts in Denmark in 1987-1991. Forensic Sci Int.
**1994**;67(3):185-195.

Kung H-C, Hanzlick R, Spitler JF. Abstracting data from medical
examiner/coroner reports: Concordance among abstractors and implications
for data reporting. J Forensic Sci. **2001**;46(5):1126-1131.

La Harpe R, Fryc O. Fatalities associated with methadone administration
in the Geneva canton (1987--1993). Arch Kriminol.
**1995**;196(1-2):24--29.

Leavitt SB. Does methadone maintenance treatment affect heart health?
Addiction Treatment Forum: Special Report (peer reviewed). June
**2001**. Available at: http://www.atforum.com.

Leavitt SB, Shinderman M, Maxwell S, Eap CB, Paris P. When "enough" is
not enough: New perspectives on optimal methadone maintenance dose. Mt
Sinai J Med. **2000**;67(5-6):404-411.

Lee CH, Berkowitz BA. Calcium antagonist activity of methadone,
l-acetylmethadol and l-pentazocine in the rat aortic strip. J Pharmacol
Exp Ther. **1977**;202(3):646-653.

Lehder DM, Arria A, Artigiani EE, Wish ED. Alcohol and drug-related
overdose deaths in Maryland: 1997-2001. College Park, MD; Center for
Substance Abuse Research (CESAR), University of Maryland: November
**2002**. Available at http://www.dewsonline.org.

Leshner AI. Drug abuse research helps curtail the spread of deadly
infectious diseases. NIDA Notes. **1999**;14(2):3-4. NIH Pub# 99-3478.

Litovitz TL, Klein-Schwartz W, Rodgers GC, et al. 2001 annual report of
the American Association of Poison Control Centers Toxic Exposure
Surveillance System. Amer J Emergency Med. **2002**;20(5):391-452.

Lobert S. Methadone may be a useful alternative for cancer pain.
Oncology Nurs Forum. **2003**;30(1):21.

Loimer N, Schmid R. The use of plasma levels to optimize methadone
maintenance treatment. Drug Alcohol Depend **1992**;30(3):241-246.

Magura S. Rosenblum A. Leaving methadone treatment: lessons learned,
lessons forgotten, lessons ignored. Mt Sinai J Med.
**2001**;68(1):62-74.

Mallinckrodt Inc. Methadose® Oral Concentrate (Methadone hydrochloride
oral concentrate USP) \[package insert\]. St. Louis, MO: Mallinckrodt
Inc; **2000**.

Mallinckrodt Inc. Methadose® Oral Tablets (Methadone hydrochloride
tablets USP; 5, 10, 40 mg) \[package inserts\]. St. Louis, MO:
Mallinckrodt Inc; **1995**.

Manfredi PL, Foley KM, Payne R, Inturrisi CE, Houde R. Parenteral
methadone: An essential medication for the treatment of pain. In
progress, **2003**.

Mantelli L, Corti V, Bini R, Cerbai E, Ledda F. Effects of dl-methadone
on the response to physiological transmitters and on several functional
parameters of the isolated guinea-pig heart. Arch Int Pharmacodyn Ther.
**1986**;282(2):298-313.

Marsch LA. The efficacy of methadone maintenance interventions in
reducing illicit opiate use, HIV risk behavior and criminality: A
meta-analysis. Addiction. **1998**;93(4):515-532.

Martell BA, Arnstein JH, Ray B, Gourevitch MN. The impact of methadone
induction on cardiac conduction in opioid users. Poster presented at:
American Association for the Treatment of Opioid Dependence Conference;
April 13-16, **2003**; Washington, DC. Poster P16.

Mathot F, Kurz X, Noel C, Firket P. Long QTc and psychotropic drugs use.
Int J Neuropsychopharmacology. **2002**;3(Suppl 1):S173. \[Abstract
P.02.18.\]

McCaffrey BR. Heroin access spurs need for methadone. USA Today. January
25, **1999**.

Merrill J. Garvey T, Rosson C. Methadone concentrations taken as
indicating deaths due to overdose need to be reviewed \[letter\]. BMJ.
**1996**;313:1481.

Mikolaenko I, Robinson A, Davis GG. A review of methadone deaths in
Jefferson County, Alabama. J For Med Path. **2002**;23(3):299-304.

Milroy CM, Forrest ARW. Methadone deaths: A toxicological analysis. J
Clin Pathol. **2000**;53:277-281.

Moody DE, Alburges ME, Parker RJ, Collins JM, Strong JM. The involvement
of cytochrome P450 3A4 in the *N*-demethylation of *L*-α-acetylmethadol
(LAAM), norLAAM, and methadone. Drug Metab Disp.
**1997**;25(12):1347-1353.

Nakamura K, Hachey DL, Kreek MJ, Irving CS, Klein PD. Quantitation of
methadone enantiomers in humans using stable isotope-labeled
\[^2^H~3~\]-, \[^2^H~5~\]-, and \[^2^H~8~\]methadone. J Pharm Sci.
**1982**;71(1):40-43.

NCHS (National Center for Health Statistics). International
Classification of Diseases, Tenth Revision (ICD-10). Available at:
http://www.cdc.gov/nchs/about/major/dvs/icd10des.htm. Updated **2002**.

Neeleman J, Farrell M. Fatal methadone and heroin overdoses: time trends
in England and Wales. Journal of Epidemiology and Community Health.
**1997**; 51:435-437.

NIDA (National Institute on Drug Abuse). Infectious diseases and drug
abuse. NIDA Notes. **1999** (August);14(2):15. NIH pub #99-3478.

NIH (National Institutes of Health). Effective Medical Treatment of
Opiate Addiction. NIH Consensus Statement. Bethesda, MD: National
Institutes of Health; **1997**(Nov 17-19);15(6):1-38. (See also: JAMA.
1998;280:1936-1943.)

Novick DM, Richman BL, Friedman JM, et al. The medical status of
methadone maintained patients in treatment for 11-18 years. Drug Alcohol
Dep. **1993**;33:235-245.

Okruhlica L, Devinsk F, Valentova J, Klempova D. Does therapeutic
threshold of methadone concentration in plasma exist? Heroin Add & Rel
Clin Probl. **2002**;4(1):29-36.

Oliver P, Keen J, Mathers N. Deaths from drugs of abuse in Sheffield
1997-1999: What are the implications for GPs prescribing to heroin
addicts? Fam Pract. **2002**;19(1):93-94.

ONDCP (Office of National Drug Control Policy). Drug Abuse in America
\[slide presentation\]. Washington, DC: Office of National Drug Control
Policy; **2002**. Available at: http://www.whitehousedrugpolicy.gov.

ONDCP (Office of National Drug Control Policy). Policy Paper: Opioid
Agonist Treatment. Washington, DC: Office of National Drug Control
Policy; **1999** (March).

ONDCP (Office of National Drug Control Policy). Methadone Fact Sheet.
Washington, DC: Office of National Drug Control Policy; **2000**
(April). Available at: http://www.whitehousedrugpolicy.gov.

ONDCP (Office of National Drug Control Policy). President\'s National
Drug Control Strategy 2003. Washington, DC: Office of National Drug
Control Policy; **2003** (February). Available at:
http://www.whitehousedrugpolicy.gov.

Parrino MW. The renaissance of methadone treatment in America. J
Maintenance in the Addictions. **2003**;2(1/2):5-17.

Payte JT. A brief history of methadone in the treatment of opioid
dependence: a personal perspective. J Psychoactive Drugs.
**1991**;23(2):103-107.

Payte JT, Khuri ET, Joseph H, Woods J. The methadone maintained patient
and the treatment of pain. CDRWG Monograph #2. Chemical Dependency
Research Working Group: The New York State Office of Alcoholism and
Substance Abuse Services. **1994**: 35-40.

Payte JT, Khuri ET. Principles of methadone dose determination. In:
Parrino MW. State Methadone Treatment Guidelines. Treatment Improvement
Protocol (TIP) Series 1. Rockville, MD: U.S. Department of Health and
Human Services; Center for Substance Abuse Treatment;**1993a**:47-58
DHHS Pub# (SMA) 93-1991.

Payte JT, Khuri ET. Treatment duration and patient retention. In:
Parrino MW. State Methadone Treatment Guidelines. Treatment Improvement
Protocol (TIP) Series 1. Rockville, MD: U.S. Department of Health and
Human Services; Center for Substance Abuse Treatment;**1993b**:119-124.
DHHS Pub# (SMA) 93-1991.

Payte JT, Zweben JE. Opioid maintenance therapies. In: Graham AW,
Schultz TK, eds. Principles of Addiction Medicine. 2nd ed. Chevy Chase,
MD: American Society of Addiction Medicine, Inc; **1998**:557-570.

Perret G, Deglon JJ, Kreek MJ, Ho A, La Harpe R. Lethal methadone
intoxications in Geneva, Switzerland, from 1994 to 1998. Addiction.
**2000**;95(11):1647-1653.

Petry NM, Bickel WK, Badger GJ. A 12-year study (1975 - 1986) of
mortality in methadone maintenance patients: Selected demographic
characteristics and drug-use patterns of AIDS and non-AIDS-related
deaths. Subst Use Misuse. **1998**; 33(12):2521-2534.

Prouty RW, Anderson WH. The forensic science implications of site and
temporal influences on postmortem blood-drug concentrations. J Forensic
Sci. **1990**;35(2):243-270.

Rendig SV, Amsterdam EA, Henderson GL, Mason DT. Comparative cardiac
contractile actions of six narcotic analgesics: morphine, meperidine,
pentazocine, fentanyl, methadone and l-alpha-acetylmethadol (LAAM). J
Pharmacol Exp Ther. **1980**;215(1):259-265.

Rettig RA, Yarmolonsky A (eds). Federal Regulation of Methadone
Treatment. Committee on Federal Regulation of Methadone Treatment;
Division of Biobehavioral Sciences and Mental Disorders; Institute of
Medicine (IOM). Washington, DC: National Academy Press; **1995**.

Robinson AE, Williams FM. The distribution of methadone in man. J Pharm
Pharmac. **1971**;23:353-358.

Roizin L, Helpern M, Baden M. Methadone fatalities in heroin addicts.
Psychiatric Quart. **1972**;46(3):393-410.

Rosenblum A, Magura S, Joseph H. Ambivalence toward methadone treatment
among intravenous drug users. J Psychoactive Drugs. **1991**;23(1):21-

Roxane Laboratories. Dolophine® Hydrochloride (Methadone Hydrochloride
Injection, USP) \[package insert\]. Manufactured by Eli Lilly and
Company. Columbus, Ohio: Roxane Laboratories, Inc; May 26, **1995**.

Roxane Laboratories. Methadone Hydrochloride Intensol™ (Oral
Concentrate, USP 10 mg/mL) \[package insert\]. Columbus, Ohio: Roxane
Laboratories, Inc; Revised February **1998**.

Roxane Laboratories. Methadone Hydrochloride Tablets USP \[package
insert\]. Columbus, Ohio: Roxane Laboratories, Inc; Revised December
**2000**.

SAMHSA (Substance Abuse and Mental Health Services Administration).
National Household Survey on Drug Abuse (NHSDA). **2001**. Available at
http://www.samhsa.gov.

SAMHSA (Substance Abuse and Mental Health Services Administration). The
Dawn Report. Narcotic Analgesics. January **2003**. Available at
http://www.samhsa.gov.

SAMHSA (Substance Abuse and Mental Health Services Administration).
Mortality Data From the Drug Abuse Warning Network, 2001. DAWN Series
D-23, **2002**. DHHS Publication No. (SMA) 03-3781. Available at
http://www.samhsa.gov.

Sanford C. Deaths from Unintentional Drug Overdoses in North Carolina,
1997-2001: A DHHS Investigation into Unintentional Poisoning-Related
Deaths. NC Injury and Violence Prevention Unit. North Carolina
Department of Health and Human Services. September 20, **2002**.

Segal RJ, Catherman RL. Methadone -- A cause of death. J Forensic Sci.
**1974**;19(1):64-71.

Seyler DE, Borowitz JL, Maickel RP. Calcium channel blockade by certain
opioids. Fundam Appl Toxicol. **1983**;3(6):536-542.

Sorg MH. Accidental methadone deaths in Maine 1997-2002. Slide
presentation and handout October 7, **2002**.

Sorg MH, Greenwald M. Maine Drug-Related Mortality Patterns:1997-2002.
State of Maine; December 27, **2002**. (Report in cooperation with the
Maine Office of the Attorney General and Maine Office of Substance
Abuse.)

Sporer KA. Acute heroin overdose. Ann Intern Med. **1999**;130:584-590.

Squires T. National confidential enquiry into methadone related deaths
(Scotland) 2000. The Scottish Executive, Health Department, Clinical
Resource and Audit Group (CRAG Ref 99/05); **2000**. Available at:
http://www.show.scot.nhs.uk/crag/topics/mhealth/NCEMRD.doc.

Stimmel B, Lipski J, Swartz M, Donoso E. Electrocardiographic changes in
heroin, methadone and multiple drug abuse: A postulated mechanism of
sudden death in narcotic addicts. Proc Natl Conf Methadone Treat.
**1973**;1:706-710. Also in: Lipski J, Stimmel B, Donoso E. The effect
of heroin and multiple drug abuse on the electrocardiogram. Amer Heart
J. 1973;86(5):663-668 \[This was an earlier analysis of the same
methadone-maintained population\].

Stine SM, Meandzija B, Kosten TR. Pharmacologic therapies for opioid
addiction. In: Graham AW, Schultz TK, eds. Principles of Addiction
Medicine. 2nd ed. Chevy Chase, MD: American Society of Addiction
Medicine, Inc; **1998**:545-555.

Symanski JD, Gettes LS. Drug effects on the electrocardiogram. A review
of their clinical importance. Drugs. **1993**;46(2):219-248.

Takehana H, Izumi T. Alcoholic heart disease \[Japanese, English
abstract\]. Nippon Rinsho. **2000**;58(1):151-156.

Tomargo J. Drug-induced torsade de pointes: from molecular biology to
bedside. Jpn J Pharmacol. **2000**;83:1-19.

Valmana A, Oyefeso A, Clancy C, Ghodse H. Methadone-related deaths: Data
from 18 coroners\' jurisdictions in England. Med Sci Law.
**2000**;40(1):61-65.

van Laar M, Crutis G, Vicente J, Frost N, Hartnoll R. EMCDDA standard
protocol for the EU member states to collect data and report figures for
the key indicator drug-related deaths by the standard reitox tables.
EMCDDA Scientific Report 20-08-2002. Lisbon Portugal: European
Monitoring Centre for Drugs and Drug Addiction; **2002**. Available at
http://www.emcdda.eu.int.

White JM, Irvine RJ. Mechanisms of fatal opioid overdose. Addiction.
**1999**;94(7):961-972.

Williamson PA, Foreman KJ, White JM, Anderson G. Methadone-related
overdose deaths in South Australia, 1984--1994. Med J Aust.
**1997**;166:302-305.

Wolff K. Characterization of methadone overdose: Clinical considerations
and the scientific evidence. Ther Drug Monit. **2002**;24(4):457-470.

Wolf K, Sanderson M, Hay AWM, Ralstrick D. Methadone concentrations in
plasma and their relationship to drug dosage. Clin Chem.
**1991**;37(2):205-209.

Wu C, Fry CH, Henry JA. Membrane toxicity of opioids measured by
protozoan motility. Toxicology. **1997a**;117:35-44.

Wu C, Fry CH, Henry JA. The mode of action of several opioids on cardiac
muscle. Exp Physiol. **1997b**;82:261-272.

Wu C, Henry JA. Interaction between ethanol and opioids in a protozoan
assay. Hum Exp Toxicol. **1994**;13:145-148.

Zador D, Sunjic S, Darke S. Heroin-related deaths in New South Wales,
1992: Toxicological findings and circumstances. Med J Australia.
**1996**;164:204-207.

Zador D Sunjic S. Deaths in methadone maintenance treatment in New South
Wales, Australia 1990-1995. Addiction. **2000**;95(1):77-84.

Zanis DA, Woody GE. One-year mortality rates following methadone
treatment discharge. Drug Alcohol Depend. **1998**;52(3):257-260.

Zickler P. 33-year study finds lifelong, lethal consequences of heroin
addiction. NIDA Notes. **2001**;16(4):1. NIH Publication No. 02-3478.

Zweben JE, Payte JT. Methadone maintenance in the treatment of opioid
dependence; A current perspective. West J Med. **1990**;152:588-599.

# Part 8. Appendices

Appendix 1. Participants in the National Assessment

Appendix 2. Agenda

Appendix 3. Epidemiologic Databases Consulted

Appendix 4. Past Investigations of Methadone-Associated Mortality

Appendix 5. Methadone Serum Level Conversion Factors

Appendix 6. MedWatch Form

Appendix 7. PedTox Case Report Form (from NAME)

Appendix 8. Methadone Identified in Laboratory Testing

# Appendix 1. Participants in the National Assessment

Co-Chairs

Bruce A. Goldberger, PhD, DABFT

Associate Professor and\
Director of Toxicology\
Departments of Pathology and Psychiatry\
College of Medicine, University of Florida\
Rocky Point Labs\
Gainesville, FL

Mark W. Parrino, MPA

President\
American Association for the Treatment of Opioid Dependence (AATOD)\
New York, NY

Seddon R. Savage, MD, FASAM

Pain Consultant, Manchester VAMC\
Project Director\
New Hampshire ReMOTE Project\
Bradford, NH\
Associate Professor of Anesthesiology\
Adjunct Faculty, Dartmouth Medical School

Participants (alphabetically)

Gavin Bart, MD

Director of Clinical Research\
Laboratory of the Biology of Addictive Diseases\
The Rockefeller University\
New York, NY

Lawrence S. Brown, Jr., MD, MPH, FASAM

President, American Society of Addiction Medicine (ASAM)\
Senior Vice President\
Addiction Research and Treatment Corporation\
Brooklyn, NY

Yale H. Caplan, PhD

Director\
National Scientific Services\
Baltimore, MD

Jennifer Collier, JD

Director of National Policy and State Strategy\
Legal Action Center\
Washington, DC

Edward J. Cone, PhD

Pinney Associates\
Bethesda, MD

Daniel S. Connolly

Director, Giuliani Partners, LLC\
New York, NY

Fiona J. Couper, PhD

Chief Toxicologist\
Office of the Chief Medical Examiner\
Government of the District of Columbia\
Washington, DC

Ed Covington, MD

Director\
Chronic Pain Rehabilitation Program\
Cleveland Clinic Foundation\
Cleveland, OH

Gregory G. Davis, MD, MSPH

Associate Professor of Pathology, Forensic Division\
University of Alabama at Birmingham\
Birmingham, AL

Ken DeCerchio, MSW, CAP

Director of Substance Abuse\
Department of Children and Families\
Tallahassee, FL

Danna E. Droz, JD

Consultant\
Frankfort, KY

Aaron M. Gilson, PhD

Assistant Director\
Pain and Policy Studies Group\
University of Wisconsin-Madison\
Madison, WI

Ann Marie Gordon, MS

Laboratory Manager\
Washington State Toxicology Laboratory\
Washington State Patrol\
Seattle, WA

Douglas Gourlay, MD, FRCP, FASAM

Medical Consultant\
Center for Addiction and Mental Health\
Toronto, Ontario; Canada

Randy L. Hanzlick, MD

Chief Medical Examiner, Fulton County, Georgia\
Associate Professor, Emory School of Medicine\
Atlanta, GA

Robert Heimer, PhD

Associate Professor of Epidemiology and Public Health and of
Pharmacology\
Yale University School of Medicine\
New Haven, CT

Howard A. Heit, MD, FACP, FASAM

Assistant Clinical Professor, Georgetown University\
Liaison Committee of Pain and Addiction\
Fairfax, VA

Jack E. Henningfield, PhD

Vice President, Research and Health Policy\
Pinney Associates\
Bethesda, MD

John D. Howard, MD

Chief Medical Examiner, Pierce County Medical Examiner's Office\
National Association of Medical Examiners\
Tacoma, WA

Jerome H. Jaffe, MD

Clinical Professor of Psychiatry\
University of Maryland School of Medicine\
Baltimore, MD

Amanda Jenkins, PhD

Chief Toxicologist\
The Office of the Cuyahoga County Coroner\
Cleveland, OH

Herman Joseph, PhD

Social Research Scientist\
National Alliance of Methadone Advocates\
New York, NY

Paul T. Kersten

General Manager, Sales and Marketing\
Roxane Laboratories, Inc.\
Bedford, OH

Mori J. Krantz, MD

Associate Professor of Medicine and Cardiology\
Denver Health\
Denver, CO

Mary Jeanne Kreek, MD

Professor, Head of Laboratory, and Senior Physician\
The Laboratory of the Biology of Addictive Diseases\
The Rockefeller University\
New York, NY

Bridget Martell, MD, MA

Medical Director\
Melrose-On-Track Clinic\
Albert Einstein College of Medicine\
Bronx, NY

Jane C. Maxwell, PhD

Research Scientist\
Gulf Coast Addiction Technology Transfer Center\
The University of Texas at Austin\
Austin, TX

Elinore McCance-Katz, MD, PhD

American Academy of Addiction Psychiatry\
Prairie Village, KS\
Professor of Psychiatry and Chair, Addiction Psychiatry\
Medical College of Virginia\
Richmond, VA

Michael Neely, MBA

Senior Product Manager, Addiction Therapy\
Tycohealthcare, Mallinckrodt, Inc.\
Hazelwood, MO

Raymond I. Pora

Sales/Marketing\
VistaPharm, Inc.\
Frankfort, IL

Catharine (Kay) Sanford, MSPH

Public Health Epidemiologist\
Injury and Violence Prevention\
Department of Health and Human Services\
State of North Carolina\
Raleigh, NC

Michael J. Schobelock, PharmD

Associate Director\
Medical Affairs Department\
Roxane Laboratories, Inc.\
Columbus, OH

Mark J. Shuman, MD, MS

Associate Medical Examiner\
Miami-Dade County Medical Examiner Department\
Miami, FL

Marcella H. Sorg, PhD, RN

Research Associate\
Margaret Chase Smith Center for Public Policy\
University of Maine\
Orono, ME

Flo Stein, MPH

Chief, Community Policy Management\
Division of Mental Health, Developmental Disabilities, and Substance
Abuse Services\
North Carolina Department of Health and Human Services\
Raleigh, NC

Barry Stimmel, MD

Editor, Journal of Addictive Disease\
Dean, Graduate Medical Education\
Mount Sinai School of Medicine\
New York, NY

Royce Watkins

Chairman and Chief Executive Officer\
Cebert Pharmaceuticals, Inc.\
Birmingham, AL

Federal Partner Participants\
(alphabetically)

Dan Budnitz, MD, MPH

EIS Officer\
National Center for Injury Prevention and Control\
Centers for Disease Control and Prevention\
Atlanta, GA

Silvia Calderon, PhD

Team Leader and Interdisciplinary Scientist\
Controlled Substance Staff\
Center for Drug Evaluation and Research\
Food and Drug Administration\
Rockville, MD

H. Westley Clark, MD, JD, MPH, CAS, FASAM

Director\
Center for Substance Abuse Treatment\
Substance Abuse and Mental Health Services Administration\
Rockville, MD

Elizabeth Crane, PhD, MPH

Service Fellow\
Drug Abuse Warning Network\
Office of Applied Studies\
Substance Abuse and Mental Health Services Administration\
Rockville, MD

Denise Curry, MA, JD

Liaison Unit Chief\
Office of Diversion Control\
Drug Enforcement Administration\
Arlington, VA

Gretchen Feussner

Pharmacologist\
Drug and Chemical Evaluation Section\
Office of Diversion Control\
Drug Enforcement Administration\
Washington, DC

Lois A. Fingerhut, MA

Special Assistant for Injury Epidemiology\
National Center for Health Statistics\
Centers for Disease Control and Prevention\
Hyattsville, MD

Angel Gonzalez, MD

Medical Officer\
Division of Pharmacologic Therapies\
Center for Substance Abuse Treatment\
Substance Abuse and Mental Health Services Administration\
Rockville, MD

Laura A. Governale, PharmD

Drug Utilization Specialist\
Office of Drug Safety\
Center for Drug Evaluation and Research\
Food and Drug Administration\
Rockville, MD

Melvyn Robert Haas, MD

Associate Director for Medical Affairs\
Center for Mental Health Services\
Substance Abuse and Mental Health Services Administration\
Rockville, MD

June E. Howard

Chief, Targeting and Analysis Unit, Drug Operations Section\
Office of Diversion Control\
Drug Enforcement Administration\
Arlington, VA

James R. Hunter, RPh, MPH

Senior Program Manager\
Controlled Substance Staff\
Center for Drug Evaluation and Research\
Food and Drug Administration\
Rockville, MD

Kirk E. James, MD

Special Expert\
Center for Substance Abuse Treatment\
Substance Abuse and Mental Health Services Administration\
Rockville, MD

T. Stephen Jones, MD

Associate Director for Prevention of Bloodborne Infections\
Centers for Disease Control and Prevention\
Atlanta, GA

Deborah B. Leiderman, MD

Director\
Controlled Substance Staff\
Center for Drug Evaluation and Research\
Food and Drug Administration\
Rockville, MD

Robert Lubran, MS, MPA

Director\
Division of Pharmacologic Therapies\
Center for Substance Abuse Treatment\
Substance Abuse and Mental Health Services Administration\
Rockville, MD

Moira O'Brien, MPhil

Program Director, Research on Emerging and Current Trends\
Division of Epidemiology, Services and Prevention Research\
National Institute on Drug Abuse\
National Institutes of Health\
Bethesda, MD

Rita Ouellet-Hellstrom, PhD

Epidemiologist\
Center for Drug Evaluation and Research\
Food and Drug Administration\
Rockville, MD

Martin L. Pollock, PharmD

Safety Evaluator\
Office of Drug Safety\
Center for Drug Evaluation and Research\
Food and Drug Administration\
Rockville, MD

Robert A. Rappaport, MD

Acting Director\
Division of Anesthetic, Critical Care and Addiction Drug Products\
Center for Drug Evaluation and Research\
Food and Drug Administration\
Rockville, MD

Nicholas P. Reuter, MPH

Division of Pharmacologic Therapies\
Center for Substance Abuse Treatment\
Substance Abuse and Mental Health Services Administration\
Rockville, MD

Barbara T. Roberts, PhD

Associate Deputy Director\
Office for Demand Reduction\
White House Office of National Drug Control Policy\
Washington, DC

Tom Schroeder, MS

Statistician\
U.S. Consumer Product Safety Commission\
Bethesda, MD

Greg Skipper, MD

National Advisory Council Member\
Center for Substance Abuse Treatment\
Medical Director\
Alabama Physician Health Program\
Montgomery, AL

Arlene Stanton, PhD, NCC

Social Science Analyst\
Division of Pharmacologic Therapies\
Center for Substance Abuse Treatment\
Substance Abuse and Mental Health Services Administration\
Rockville, MD

Richard T. Suchinsky, MD

Associate Chief for Addictive Disorders\
Department of Veterans Affairs\
Washington, DC

Alan Trachtenberg, MD, MPH

Medical Officer\
Division of Pharmacologic Therapies\
Center for Substance Abuse Treatment\
Substance Abuse and Mental Health Services Administration\
Rockville, MD

Frank J. Vocci, PhD

Director\
Division of Treatment Research and Development\
National Institute on Drug Abuse\
National Institutes of Health\
Bethesda, MD

Celia Jaffe Winchell, MD

Medical Team Leader, Addiction Drug Products\
Division of Anesthetic, Critical Care, and Addiction Drug Products\
Center for Drug Evaluation and Research\
Food and Drug Administration\
Rockville, MD

# Appendix 2. Agenda

**Thursday, May 8, 2003**

Introductions:\
*Alan Trachtenberg, MD, MPH; Medical Officer, DPT/CSAT/SAMHSA*

Opening Remarks: The CSAT Perspective:\
*H. Westley Clark, MD, JD, MPH, CAS, FASAM; Director, CSAT*

The Opioid Treatment Program (OTP) Perspective:\
*Mark W. Parrino, MPA, President, AATOD (OTP Co-Chair)*

Clinical Importance of Methadone in Opioid Agonist Therapy (OAT)\
and Pain Management:\
*Seddon R. Savage, MD, FASAM (Pain Co-Chair)*

Challenges to the Forensic Community:\
*Bruce Goldberger, PhD (Toxicology Co-Chair)*

Drug Abuse Warning Network (DAWN) and other SAMHSA Office of Applied\
Studies (OAS) Data:\
*Elizabeth Crane, PhD, MPH*

Opioid Utilization (Denominator) Data:\
ARCOS: *June Howard, DEA, & Alan Trachtenberg, CSAT\
*NCHS Outpatient Utilization Data: *Catharine Burt, EdD, NCHS\
*IMS: *Laura Governale, PharmD, FDA*

Methadone Mortality Data from MedWatch (Passive National Surveillance):\
*Martin L. Pollock, PharmD, FDA*

Surveillance of Medication-Related Mortality and Morbidity (Current
efforts of the National Center for Injury Prevention and Control):\
*Dan Budnitz, MD, MPH*

Cardiac Questions (QT prolongation, TdP):\
Background: *Mori Krantz, MD\
*New Population-based Data: *Bridget Martell, MD\
*Discussion: *Barry Stimmel, MD*

Trends in Fatal Opioid Poisoning - National Numerator and Death
Certificate Data:\
*Lois Fingerhut, MA, NCHSR*

State-Level Data:\
Florida: *Bruce Goldberger, PhD*\
North Carolina: *Kay Sanford, MSPH*\
Maine: *Marcella Sorg, RN, PhD*\
Washington & Virginia: *Ann Marie Gordon, BA, MS*\
Texas: *Jane Maxwell*

Discussion Breakout Meetings (3 Interdisciplinary Groups):\
Questions for resolution:\
-- What are the problems?\
-- Which drugs and persons are involved?\
-- What further data are needed? Why?\
-- Where should data come from?\
-- How should the data be organized?\
-- How can the data help in developing action plans?

Group Reports & Discussion

**Friday, May 9, 2003**

Overview:

*H. Westley Clark, MD, JD, MPH, CAS, FASAM; Director, CSAT*

The Challenge for the Morning:\
*Seddon R. Savage, MD, FASAM*

Relevant New Efforts at Data Collection:\
National Violent Death Reporting System (NVDRS): *Randy Hanzlick, MD\
*NAME Pediatric Toxicology Registry: *John Howard, MD\
*Consumer Product Safety Commission: *Tom Schroeder, MS*\
Electronic Prescription Monitoring Systems: *Danna Droz*

Developing Relationships Between Medical Examiner & Medical Practitioner
-- A report from Canada:\
*Doug Gourlay, MD*

Action Planning Breakout Sessions (3 Intra-disciplinary Groups):
Forensics (Pathology & Toxicology), Addiction Treatment, Pain
Treatment:\
General questions for resolution:\
-- Are there actions that could/should be taken immediately?\
-- What are longer-range goals?\
-- How can each "community"/ disciplinary group contribute?\
-- What resources, programs, or services (RPS) already exist?\
-- What new RPSs can/should be developed? Why?\
-- Who are the target audiences?\
-- How should outcomes be monitored?

Group Reports from Breakout Sessions

Brief Statements from Organization representatives (NAME, AAFS, SOFT,
ASAM, AAAP, AAPM, etc.):\
*Open invitation for voluntary additions to the record (proceedings)\
from the national organizations represented at the meeting.*

Closing: Where do we go from here?\
*Mark W. Parrino, MPA*

# Appendix 3. Epidemiologic Databases Consulted

+-----------+----------------------------------------------------------+
| **        |                                                          |
| Databases |                                                          |
| C         |                                                          |
| ontaining |                                                          |
| In        |                                                          |
| formation |                                                          |
| Relevant  |                                                          |
| to Opioid |                                                          |
| Pre       |                                                          |
| scribing, |                                                          |
| Use,      |                                                          |
| Abuse,    |                                                          |
| Ov        |                                                          |
| erdose/Po |                                                          |
| isonings, |                                                          |
| and       |                                                          |
| Fat       |                                                          |
| alities** |                                                          |
+===========+==========================================================+
| **        | The Substance Abuse and Mental Health Services           |
| *SAMHSA - | Administration (SAMHSA), Office of Applied Studies (OAS) |
| OAS***    | is a source of information on the prevalence and         |
|           | incidence of substance abuse and mental health problems  |
|           | in the U.S. and the characteristics of those who suffer  |
|           | from these problems. SAMHSA's OAS is also the national   |
|           | source of information on the location, organization, and |
|           | capacity of providers which offer services to prevent    |
|           | and treat substance abuse and the cost, quality, and     |
|           | effectiveness of the services of these providers. For    |
|           | more information on the various surveys and reports see: |
|           | http://www.samhsa.gov.                                   |
+-----------+----------------------------------------------------------+
| **NSDUH\  | The National Survey on Drug Use and Health (NSDUH) has   |
| **        | been conducted since 1971 and serves as the primary      |
| *(NHSDA)* | source of information on the prevalence and incidence of |
|           | illicit drug, alcohol, and tobacco use, as well as the   |
|           | non-medical use of licit drugs, in the civilian,         |
|           | noninstitutionalized population aged 12 or older in the  |
|           | U.S. Information about substance abuse and dependence,   |
|           | mental health problems, and receipt of substance abuse   |
|           | and mental health treatment also is included. Since      |
|           | 1999, about 70,000 interviews are conducted each year.   |
|           | Before 2002, the name of the survey was the National     |
|           | Household Survey on Drug Abuse (NHSDA).                  |
+-----------+----------------------------------------------------------+
| **DAWN**  | The Drug Abuse Warning Network (DAWN) provides           |
|           | semiannual estimates of the number of drug-related       |
|           | visits to hospital emergency departments based on a      |
|           | nationally representative sample of short-stay general   |
|           | hospitals located throughout the coterminous United      |
|           | States. DAWN also collects information on drug-related   |
|           | deaths from selected medical examiner offices. Emergency |
|           | room estimates are produced for 21 large metropolitan    |
|           | areas and for the nation, while drug-related death data  |
|           | are produced for more than 40 metropolitan areas.        |
+-----------+----------------------------------------------------------+
| **DASIS** | The Drug and Alcohol Services Information System (DASIS) |
|           | is the primary source of national data on substance      |
|           | abuse treatment and has three components:                |
+-----------+----------------------------------------------------------+
| *I-SATS*  | The Inventory of Substance Abuse Treatment Services      |
|           | (I-SATS) is a listing of all known public and private    |
|           | substance abuse treatment facilities in the United       |
|           | States and its territories. Before 2000, the I-SATS was  |
|           | known as the National Master Facility Inventory.         |
+-----------+----------------------------------------------------------+
| *N-SSATS\ | The National Survey of Substance Abuse Treatment         |
| (UFDS)*   | Services (N-SSATS) is an annual survey of all facilities |
|           | in the I-SATS that collects information on location,     |
|           | characteristics, services offered and utilization.       |
|           | Information from the N-SSATS is used to compile and      |
|           | update the National Directory of Drug and Alcohol Abuse  |
|           | Treatment Programs and the on-line Substance Abuse       |
|           | Treatment Facility Locator. The N-SSATS includes a       |
|           | periodic survey of substance abuse treatment in adult    |
|           | and juvenile correctional facilities. Before 2000, the   |
|           | N-SSATS was known as the Uniform Facility Data Set       |
|           | (UFDS).                                                  |
+-----------+----------------------------------------------------------+
| *TEDS*    | The Treatment Episode Data Set (TEDS) is a compilation   |
|           | of data on the demographic and substance abuse           |
|           | characteristics of admissions to substance abuse         |
|           | treatment. Information on treatment admissions is        |
|           | routinely collected by State administrative systems and  |
|           | then submitted to SAMHSA in a standard format.           |
+-----------+----------------------------------------------------------+
| **DSRS**  | The Drug Services Research Survey ( DSRS) is a national  |
|           | survey which obtained information on drug treatment      |
|           | providers and patients in 1990. The survey consisted of  |
|           | several components, a facility-based telephone interview |
|           | with a sample of 1,183 drug treatment providers followed |
|           | by a patient record-based survey of 2,200 patients       |
|           | discharged from treatment in a sub-sample of the         |
|           | programs. Follow-up of the patients to assess            |
|           | post-treatment status was conducted in the Services      |
|           | Research Outcomes Study (SROS).                          |
+-----------+----------------------------------------------------------+
| **SROS**  | The Services Research Outcome Study (SROS) is a          |
|           | follow-on to the 1990 Drug Services Research Survey      |
|           | (DSRS). The SROS provided for a five-year post-discharge |
|           | follow-up of a broadly representative sample of          |
|           | approximately 3,000 drug abuse patients treated during   |
|           | 1989 to 1990. The study ascertained their behavior up to |
|           | five years after the 1989-1990 treatment episode, and    |
|           | analyzes treatment results in light of the type and cost |
|           | of treatment services the patients received.             |
+-----------+----------------------------------------------------------+
| **ADSS**  | The Alcohol and Drug Services Study (ADSS) is a          |
|           | nationally representative survey of substance abuse      |
|           | treatment facilities and patients. The data were         |
|           | collected to estimate the patient length of stay and the |
|           | costs of treatment as well as to describe the            |
|           | post-treatment status of patients. ADSS builds upon the  |
|           | 1990 Drug Services Research Survey (DSRS) and the        |
|           | Services Research Outcome Study (SROS) with a more       |
|           | complete sampling frame, an enhanced sampling design,    |
|           | and more detailed measures of the level of treatment     |
|           | services provided, the costs of treatment, and patients  |
|           | in treatment.                                            |
+-----------+----------------------------------------------------------+
| ***DEA*** | U.S. Drug Enforcement Administration                     |
|           |                                                          |
| **ARCOS** | The Automation of Reports and Consolidated Orders System |
|           | (ARCOS) is an automated, comprehensive drug reporting    |
|           | system that monitors the flow of controlled substances   |
|           | from their point of manufacture through commercial       |
|           | distribution channels to point of sale or distribution   |
|           | at the dispensing/retail level by hospitals, retail      |
|           | pharmacies, practitioners, mid-level practitioners, and  |
|           | teaching institutions. Included in the list of           |
|           | controlled substance transactions tracked by ARCOS are   |
|           | the following: All Schedules I and II materials          |
|           | (manufacturers and distributors); Schedule III narcotic  |
|           | materials (manufacturers and distributors); and selected |
|           | Schedule III and IV psychotropic drugs (manufacturers    |
|           | only).                                                   |
|           |                                                          |
|           | ARCOS accumulates these transactions which are then      |
|           | summarized into reports which give investigators in      |
|           | Federal and State government agencies information which  |
|           | can then be used to identify the diversion of controlled |
|           | substances into illicit channels of distribution.        |
|           |                                                          |
|           | Available at:                                            |
|           | http://www.deadiversion.usdoj.gov/arcos/index.html.      |
+-----------+----------------------------------------------------------+
| **NFLIS** | The National Forensics Laboratory Information System     |
|           | (NFLIS) from the DEA systematically collects results     |
|           | from drug analyses conducted by State and local forensic |
|           | laboratories, and reflects drug evidence seized by law   |
|           | enforcement agencies. Results in this report are         |
|           | presented for both drug items and drug cases.            |
|           |                                                          |
|           | Approximately 300 State and local forensic laboratories  |
|           | in the United States analyze nearly 2 million drug items |
|           | each year. The Drug Enforcement Administration (DEA) has |
|           | long recognized that these analyses represent valuable   |
|           | information. The current partnership includes 34 State   |
|           | lab systems and 49 local or municipal labs, a total of   |
|           | 179 individual labs.                                     |
|           |                                                          |
|           | See:                                                     |
|           | http://www.deadiversion.usdoj.gov/nflis/overview.htm.    |
+-----------+----------------------------------------------------------+
| **        | Office of National Drug Control Policy, The White House  |
| *ONDCP*** |                                                          |
+-----------+----------------------------------------------------------+
| **        | An annual report to Congress compiles data from a        |
| National\ | variety of sources relating to drug misuse and abuse in  |
| Drug\     | the U.S., as well as Administration strategies and       |
| Control\  | budgets to address the problem.\                         |
| S         | See http://www.whitehousedrugpolicy.gov/index.html.      |
| trategy** |                                                          |
+-----------+----------------------------------------------------------+
| **DENS**  | The Drug Evaluation Network System (DENS) is an          |
|           | electronic information system to track national trends   |
|           | in substance abuse treatment sponsored by the White      |
|           | House Office of National Drug Control Policy (ONDCP) and |
|           | the Center for Substance Abuse Treatment (CSAT). It is a |
|           | collaborative effort between the Treatment Research      |
|           | Institute (TRI) at the University of Pennsylvania and    |
|           | the National Center on Addiction and Substance Abuse     |
|           | (CASA) at Columbia University. The goal of the project   |
|           | is to provide practical and current clinical and         |
|           | administrative information on patients entering into     |
|           | substance abuse treatment throughout the nation.         |
|           |                                                          |
|           | Through the RADARS System (see below), Purdue Pharma     |
|           | provided funding in 2002 to add questions to the DENS    |
|           | questionnaire about prescription drugs identified by     |
|           | individuals entering addiction treatment programs.       |
|           |                                                          |
|           | See http://www.densonline.org/ for more information.     |
+-----------+----------------------------------------------------------+
| ***FDA*** | U.S. Food and Drug Administration                        |
|           |                                                          |
| **M       | MedWatch, the FDA's Safety Information and Adverse Event |
| edWatch** | Reporting Program, serves both health care professionals |
|           | and the public. It provides clinical information about   |
|           | safety issues involving medical products, including      |
|           | prescription and over-the-counter drugs, biologics,      |
|           | medical and radiation-emitting devices, and special      |
|           | nutritional products. MedWatch allows healthcare         |
|           | professionals and consumers to report serious problems   |
|           | that they suspect are associated with the drugs and      |
|           | medical devices they prescribe, dispense, or use.        |
|           |                                                          |
|           | See: http://www.fda.gov/medwatch/index.html              |
+-----------+----------------------------------------------------------+
| ***NCHS - | National Center for Health Statistics / Centers for      |
| CDC\      | Disease Control and Prevention\                          |
| ***       | See: http://www.cdc.gov/nchs/about/major/ahcd/ahcd1.htm  |
|           |                                                          |
| **NAMCS** | The National Ambulatory Medical Care Survey (NAMCS) is   |
|           | designed to meet the need for objective, reliable        |
|           | information about the use of ambulatory medical care     |
|           | services in the United States. Findings are based on a   |
|           | sample of visits to nonfederally employed office-based   |
|           | physicians who are primarily engaged in direct patient   |
|           | care. The survey was conducted annually from 1973 to     |
|           | 1981, in 1985, and annually since 1989.                  |
+-----------+----------------------------------------------------------+
| *         | The National Hospital Ambulatory Medical Care Survey     |
| *NHAMCS** | (NHAMCS) collects data on the utilization and provision  |
|           | of ambulatory care services in hospital emergency and    |
|           | outpatient departments. Findings are based on a national |
|           | sample of visits to the emergency departments and        |
|           | outpatient departments of noninstitutional general and   |
|           | short-stay hospitals, exclusive of Federal, military,    |
|           | and Veterans Administration hospitals, located in the 50 |
|           | States and the District of Columbia. Annual data         |
|           | collection began in 1992.                                |
+-----------+----------------------------------------------------------+
| **CDC\    | CDC's WONDER is an easy-to-use system that provides a    |
| WONDER**  | single point of access to a wide variety of CDC reports, |
|           | guidelines, and numeric public health data, including:   |
|           | mortality, hospital discharges, behavioral risk factors, |
|           | and many other topics.                                   |
|           |                                                          |
|           | See: http://wonder.cdc.gov/                              |
+-----------+----------------------------------------------------------+
| **        | American Association of Poison Control Centers           |
| *AAPCC*** |                                                          |
|           | Toxic Exposure Surveillance Systems (TESS) data are      |
| **TESS**  | compiled by the AAPCC. From its inception in 1983, TESS  |
|           | has grown dramatically, with the cumulative database in  |
|           | 2001 containing 31.4 million human poison exposure       |
|           | cases, including about 2.3 million for 2001 alone        |
|           | reported by 64 participating poison centers covering 48  |
|           | States and the District of Columbia.                     |
|           |                                                          |
|           | See: http://www.aapcc.org/annual.htm                     |
+-----------+----------------------------------------------------------+
| **IMS**   | Operating in more than 100 countries, IMS Health, a      |
|           | leading provider of information to the pharmaceutical    |
|           | and healthcare industries, offers marketing data on      |
|           | prescription and over-the-counter pharmaceutical         |
|           | products.                                                |
|           |                                                          |
|           | IMS tracks and measures prescriptions dispensed along    |
|           | with sales volumes, pricing and market share -- by       |
|           | product, company, region and distribution channel.       |
|           | Customized measures of market performance include:       |
|           | Daily, weekly and monthly prescription tracking; key     |
|           | physician prescribing patterns.                          |
|           |                                                          |
|           | Additional information is available at                   |
|           | http://www.imshealth.com.                                |
+-----------+----------------------------------------------------------+
| *         | Purdue Pharma established the Researched Abuse,          |
| *RADARS** | Diversion and Addiction-Related Surveillance (RADARS)    |
|           | System in 2002 to study the prevalence of abuse and      |
|           | diversion of controlled prescription medications. The    |
|           | system is designed to obtain quantitative and            |
|           | qualitative information on the relative rates of abuse,  |
|           | addiction, and diversion of commonly prescribed          |
|           | prescription pain medicines.                             |
|           |                                                          |
|           | Initially, the RADARS System was to monitor six types of |
|           | prescription opioid pain medications with recognized     |
|           | abuse potential: morphine, buprenorphine, fentanyl,      |
|           | hydrocodone, hydromorphone, and oxycodone. As experience |
|           | with the system accumulates, other types of medications, |
|           | such as benzodiazepines (alprazolam and diazepam), are   |
|           | to be added. This database is not open to the public.    |
|           |                                                          |
|           | See: http://www.purduepharma.com.                        |
+-----------+----------------------------------------------------------+
| ***OT     | The National Violent Death Reporting System (NVDRS) is a |
| HER...*** | State-based initiative, funded by the CDC, which tracks  |
|           | violent deaths resulting from the use of physical force, |
| **NVDRS** | either intentional or unintentional: homicide, suicide,  |
|           | firearm accidents, legal interventions, terrorism, etc.  |
|           | Within that, there is a Medical Examiner/Coroner Death   |
|           | Investigation Data Set (MECDIDS) providing standard      |
|           | fields for data collection. Another component -- BLURBS  |
|           | -- is a coding scheme allowing searches for specific     |
|           | toxicology data.                                         |
+-----------+----------------------------------------------------------+
| **NAME\   | The National Association of Medical Examiners' (NAME)    |
| PedTox\   | Pediatric Toxicology (PedTox) Registry represents        |
| R         | jurisdictions from around the U.S. and contains detailed |
| egistry** | case description information beyond what can be found in |
|           | death certificate data. Reporting is voluntary and       |
|           | toxicologic data are not standardized.                   |
+-----------+----------------------------------------------------------+
| **CPS     | The Consumer Product Safety Commission (CPSC) uses death |
| C/NEISS** | certificate data for a National Electronic Injury        |
|           | Surveillance System (NEISS). The Commission also used    |
|           | NCHS (National Center for Health Statistics) data to     |
|           | estimate causes of death for specific product-related    |
|           | accidents. This includes drug-related accidents, and     |
|           | specific studies can be done on request to evaluate      |
|           | specific agents.                                         |
+-----------+----------------------------------------------------------+
| **PMPs**  | Prescription Monitoring Programs (PMPs) have been        |
|           | implemented by a number of States to collect data for    |
|           | public health initiatives, law enforcement, and early    |
|           | intervention and prevention of problems related to       |
|           | diversion and abuse of prescription drugs. PMPs rely on  |
|           | pharmacies and other drug dispensers to send data        |
|           | electronically to central state-managed repositories.    |
+-----------+----------------------------------------------------------+
| **N       | The National Institute of Justice\'s (NIJ) Arrestee Drug |
| IJ/ADAM** | Abuse Monitoring (ADAM) program tracks trends in the     |
|           | prevalence and types of drug use among booked arrestees  |
|           | in urban areas. The data play an important role in       |
|           | assembling a national picture of drug abuse in the       |
|           | arrestee population and have been a central component in |
|           | studying the links between drug use and criminal         |
|           | behavior. See: http://www.adam-nij.net/                  |
+-----------+----------------------------------------------------------+

# Appendix 4. Past Investigations of Methadone-Associated Mortality 

  -------------------------------------------------------------------------------------------------
  **Epidemiologic /                                                 
  Descriptive Studies of                                            
  Methadone-Associated                                              
  Mortality**                                                       
  ---------------------- ------------------- ---------------------- -------------------------------
  **Reference**          **Location/Date**   **Subjects/Design**    **Comments**

  Dole et al., 1971      New York,\          Series of 2 cases in a Accidental overdose not
                         1960s               methadone program.     otherwise specified.

  Gardner, 1970          London,\            Descriptive study of   Concludes that at least 7
                         1965-1969           12 methadone deaths.   deaths occurred due to lack of
                                                                    opioid tolerance, while 8
                                                                    resulted from too high a
                                                                    starting dose (greater than 70
                                                                    mg).

  Baden, 1970            New York,\          Report on 24 deaths in Half of the methadone deaths
                         1967-1970           a methadone program    were related to abuse of
                                             and 8 not in OTP.      alcohol and other drugs. Of 8
                                                                    methadone-associated deaths
                                                                    outside OTP, 5 involved oral
                                                                    overdoses (2 in opioid-naïve
                                                                    subjects), 3 involved IV abuse
                                                                    of methadone.

  Gearing and            New York,\          Long-term descriptive  Causes of death in 153 subjects
  Schweitzer, 1974       1964-1971           study on outcomes of   are not detailed, but at least
                                             subjects in OAT.       30 percent were
                                                                    polydrug-related.

  Roizin et al., 1972    New York,\          Series of 14 deaths,   Methadone doses ranged from
                         1972                57 percent of whom     40-180 mg/d. Polydrug abuse was
                                             were receiving         implicated in most cases,
                                             methadone.             including morphine (4) and
                                                                    quinine (2).

  Greene et al., 1974    District of         Descriptive study of   Methadone deaths increased
                         Columbia,\          methadone death rate.  sharply following diversion to
                         1970-1973                                  illicit markets -- 46.2 percent
                                                                    of decedents were not
                                                                    opioid-tolerant -- and were
                                                                    curtailed sharply by
                                                                    restricting dispensing to
                                                                    licensed clinics rather than
                                                                    private physicians.

  Appel et al., 2000     New York,\          176 deaths among 1,544 Overall, 93 deaths occurred
                         1966-1976           patients in and out of during methadone treatment and
                                             OAT program.           83 after leaving treatment.
                                                                    Only 2 deaths during treatment
                                                                    were opioid-related.

  Concool et al., 1979   East Harlem, NY,\   Review of deaths in    The mortality rate was 20 per
                         1969-1976           patients enrolled in   1000 patients, with deaths
                                             OAT, with risk         largely due to alcoholism and
                                             assessment.            violence. None of the deaths
                                                                    were directly attributed to
                                                                    methadone.

  Caplan et al., 1983    Maryland,\          77 deaths in which     Methadone was the sole agent in
                         1975-1980           methadone was present. 18 deaths. There was an overlap
                                                                    in serum methadone levels
                                                                    across sole-agent deaths,
                                                                    polydrug deaths, and
                                                                    non-drug-related deaths with
                                                                    methadone present.

  Kringsholm et al.,     Denmark,\           Descriptive study of   20 percent of drug deaths
  1988                   1968-1986           drug deaths.           during abstinence were due to
                                                                    methadone. No details of
                                                                    circumstances were provided.

  Petry et al.,\         New York,\          Review of 325 deaths   During a 12-year period, deaths
  1998                   1975-1986           among OAT patients     attributed to medical causes
                                             receiving methadone.   (especially AIDS) dramatically
                                                                    increased, while drug overdose
                                                                    deaths held fairly constant at
                                                                    low levels.

  Harding-Pink, 1991     Geneva,             Description of 25      14 deaths were caused by
                         Switzerland,\       deaths associated with methadone, of which 3 occurred
                         1981-1986           methadone.             in the first two weeks of
                                                                    treatment and 6 less than two
                                                                    weeks after leaving treatment;
                                                                    9 were caused by a combination
                                                                    of opioids and methadone. 15
                                                                    deaths were associated with
                                                                    concurrent benzodiazepine use.

  Davoli et al., 1993    Italy,\             Matched case control   The risk of overdose death was
                         1980-1988           analysis of IV drug    higher for subjects who had
                                             abusers in OAT.        left methadone treatment,
                                                                    particularly within the first
                                                                    year (odds ratio: 7.98).

  Drummer et al., 1990,  Victoria,\          10 deaths in           Deaths occurred in the early
  1992                   Australia, 1990     methadone-treated      stages of OAT, at doses ranging
                                             patients.              from 45-70 mg (mean: 53 mg).
                                                                    Six subjects had additional
                                                                    CNS-active drugs present; all
                                                                    had chronic hepatitis; 5 had
                                                                    bronchopneumonia.

  Kringsholm, et al.     Denmark,\           Descriptive study of   Against a background of
  1994                   1987-1991           drug deaths.           increasing fatalities, with
                                                                    most also involving IV heroin,
                                                                    methadone poisoning cases
                                                                    increased significantly in
                                                                    1991. About half the victims
                                                                    were on methadone maintenance
                                                                    at the time of death.

  Neeleman and Farrell,  England and\        Retrospective          Poisoning deaths involving
  1997                   Wales,\             longitudinal survey.   methadone (alone or in
                         1974-1992                                  combination) rose 80 percent
                                                                    over a 3-year period. However,
                                                                    there was no evidence that this
                                                                    was disproportionate to the
                                                                    increase in heroin deaths.

  Barrett et al., 1996   Harris County,      Investigation of 91    A team of CDC investigators
                         Texas,\             deaths involving       found that 85 percent of deaths
                         1987-1992           methadone.             involved polydrug abuse and
                                                                    only 20 percent of decedents
                                                                    were in OAT at the time of
                                                                    death. Only 11 cases were
                                                                    attributed directly to
                                                                    methadone toxicity.

  La Harpe and Fryc,     Geneva,             Description of 24      No deaths occurred in first two
  1995                   Switzerland,\       deaths associated with weeks of methadone treatment, 3
                         1987-1993           methadone.             occurred less than 2 weeks
                                                                    after leaving OAT, 11 involved
                                                                    concurrent use of
                                                                    benzodiazepines, 8 involved
                                                                    concurrent use of alcohol, and
                                                                    11 iinvolve concurrent use of
                                                                    heroin.

  Goldstein and          Albuquerque,\       Long-term follow-up of 34 percent of patients died in
  Herrera,1995           1971-1993           1,019 patients         the 22 years since starting
                                             registered in          methadone therapy. More than a
                                             methadone OAT.         third of the deaths were
                                                                    related to drug abuse. Subjects
                                                                    were 4-6 times more likely to
                                                                    die than non-addicts.

  Clark et al., 1995     Sheffield,          18 subjects; case      7 subjects died in the early
                         England,\           study.                 stages of methadone treatment
                         1991-1994                                  (and had received doses in the
                                                                    range of 30-100 mg). 3 died
                                                                    after long-term use and 8 died
                                                                    from non-prescribed drug use.
                                                                    Multiple drug use was common
                                                                    but was not judged to have
                                                                    played a major role in most
                                                                    deaths.

  Cairns et al., 1996    Manchester,         90 subjects; case      The number of methadone deaths
                         England,\           study.                 increased in during the study
                         1985-1994                                  period. Methadone was the sole
                                                                    cause of death in 52 cases,
                                                                    while 36 died from other drug
                                                                    use. Methadone cases
                                                                    represented 15 percent of total
                                                                    fatal drug overdoses during the
                                                                    study period.

  Williamson et al.,     South Australia,\   47 fatalities, with    Widespread use of methadone
  1997                   1984-1994           risk assessment.       tablets for chronic pain led to
                                                                    a disproportionate increase in
                                                                    deaths . The death rate
                                                                    increased sharply in 1993-94
                                                                    concurrent with the opening of
                                                                    private methadone clinics.

  Caplehorn, 1998        Sydney , Australia, 13 subjects; case      Of 13 patient deaths, 10 died
                         1994                study.                 in the first two weeks of
                                                                    treatment, during methadone
                                                                    induction; doses ranged from
                                                                    25-110 mg (median: 40 mg).

  Caplehorn and Drummer, Sydney, Australia,  Review of 86           Of 89 deaths, 29 involved
  1999                   1994                methadone-associated   diversion of methadone syrup
                                             deaths; risk           and 18 the use of methadone
                                             assessment.            tablets. 38 patients died
                                                                    during OAT. The risk of death
                                                                    in the first 2 weeks was 6.7
                                                                    times that of addicts outside
                                                                    OAT, but was reduced 98-fold
                                                                    later during methadone
                                                                    maintenance treatment.

  Zador and Sunjic, 2000 New South Wales,    238                    44 percent of deaths were
                         Australia,\         methadone-associated   drug-related, with most (92
                         1990-1995           deaths examined.       percent) involving polydrug
                                                                    abuse; 42 percent occurred
                                                                    during the first week of
                                                                    methadone treatment.

  Drummer, 1997          Victoria,           89 deaths in which     Toxic methadone concentrations
                         Australia,\         methadone was          overlapped those in
                         1994-1997           detected.              non-drug-related deaths in
                                                                    which methadone was present.
                                                                    Those starting OAT or who used
                                                                    the drug occasionally were at
                                                                    the greatest risk of death.

  Valmana et al., 2000   London, England,    Review of 40           Of 40 methadone-related deaths,
                         1997                methadone-associated   72 percent did not involve
                                             deaths.                prescribed methadone. These
                                                                    decedents were younger (median
                                                                    age: 22 years) than those who
                                                                    died of prescribed methadone
                                                                    (median age: 37 years),
                                                                    suggesting more chaotic abuse
                                                                    patterns in younger persons.

  Perret et al., 2000    Geneva,             36 methadone cases,    35 of 36 decedents used illicit
                         Switzerland,\       out of 106 total drug  drugs in combination with
                         1994-1998           abuse fatalities.      methadone. Of 21 deaths
                                                                    attributed to methadone, only a
                                                                    third of those decedents were
                                                                    in OAT. Methadone-attributed
                                                                    deaths remained constant at 3-5
                                                                    per year throughout the study
                                                                    period, while overall drug
                                                                    abuse deaths declined markedly.

  Eastwood, 1998         London, England,    Description of 13      Of 13 children poisoned with
                         1998                childhood deaths.      methadone syrup prescribed to a
                                                                    parent, five died. Methadone
                                                                    serum concentrations in
                                                                    children who died overlapped
                                                                    that in children who survived.

  Karch and Stephens,    San Francisco,\     38 cases involving     Methadone was cited as a cause
  2000                   1997-1998           methadone (out of      of death in 21 cases, although
                                             3,317 examined).       blood methadone concentrations
                                                                    were identical in this group
                                                                    and in the group in whom
                                                                    methadone was an incidental
                                                                    finding.

  Buster et al., 2002    Amsterdam, The      5,200                  68 overdose deaths were
                         Netherlands,\       methadone-maintained   recorded in a group of 5,200
                         1986-1998           patients observed.     methadone patients, with a
                                                                    modest increase during first 2
                                                                    weeks of treatment. The overall
                                                                    death rate was 2.3 per 1000
                                                                    patient-years.

  Heinemann et al., 2000 Hamburg, Germany,\  Surveillance of        An increase in
                         1990-1999           drug-related           methadone-related fatalities
                                             poisonings.            coincided with declines in
                                                                    heroin deaths. 65 percent of
                                                                    methadone decedents were not
                                                                    enrolled in an OTP.

  Bartu et al., 2002     Western Australia,\ 84 methadone-related   74 percent of deaths were
                         1993-1999           deaths evaluated.      caused by a combination of drug
                                                                    effects, with benzodiazepines
                                                                    present in 75 percent of those
                                                                    cases. 57 percent were not in
                                                                    an OTP at the time of death.
                                                                    Methadone-associated mortality
                                                                    peaked in 1998 at 7.7 per 1000
                                                                    patients treated, one year
                                                                    after expansion into the
                                                                    private sector.

  Green et al., 2000     South Australia,\   35 cases of methadone  Of 10 patients receiving
                         1996-1999           causing or             methadone maintenance
                                             contributing to death. treatment, 4 died within the
                                                                    first week. Eight non-OAT cases
                                                                    involved diverted methadone,
                                                                    while 7 involved other drugs as
                                                                    well. Mean age of the decedents
                                                                    was 25 years.

  Oliver et al., 2002    Sheffield,          82 drug-abuse related  Deaths attributed wholly or
                         England,\           deaths.                partially to methadone declined
                         1997-1999                                  from 37 percent to 18 percent
                                                                    during the study period,
                                                                    against a background of
                                                                    increased methadone
                                                                    prescribing.

  Squires,\              Scotland,\          Surveillance report on Methadone deaths peaked in 1996
  2000                   1994-2000           methadone-related      and then declined, while
                                             deaths.                methadone prescriptions
                                                                    increased by 18 percent. 45
                                                                    percent of deaths involved
                                                                    persons not prescribed
                                                                    methadone, all but 2 involved
                                                                    drug abuse-related causes, and
                                                                    there were no deaths within one
                                                                    month of starting methadone
                                                                    maintenance. Of decedents who
                                                                    were prescribed methadone, 60
                                                                    percent were on observed dosing
                                                                    at the time of death.
  -------------------------------------------------------------------------------------------------

# Appendix 5. Methadone Serum Level Conversion Factors

In the literature, there does not appear to be a universally accepted
standard for expressing the concentration of methadone (or other agents)
detected in the blood of living or deceased subjects, and authors have
used diverse measures of notation. Nanograms per milliliter (ng/mL)
seems to be the accepted convention in the United States addiction
treatment literature; therefore, all values noted in this report have
been converted to that measure using the following factors:

> [Unit 1.0]{.underline}\
> deci- d 1 x 10^-1^ 0.1\
> centi- c 1 x 10^-2^ 0.01\
> milli- m 1 x 10^-3^ 0.001\
> micro- μ 1 x 10^-6^ 0.000001\
> nano- n 1 x 10^-9^ 0.000000001
>
> **μg/L** -- 1 μg/L = 1000 ng/1000 mL = 1 ng/mL
>
> **μg/mL** -- 1 μg/mL = 1000 ng/mL\
> (1 ng/mL = 0.001 μg/mL)
>
> **mg/L** -- 1 mg/L = 1000 ng/mL\
> (1 ng/mL = 0.001 mg/L)
>
> **mg/dL** -- 1 mg/dL = 10,000 ng/mL\
> (1 ng/mL = 0.0001 mg/dL)
>
> **mg%** -- 1 mg% = 1 mg/100 mL = 10,000 ng/mL\
> (1 ng/mL = .0001 mg%)
>
> **μmol** -- 1 μmol = 345 ng/mL\
> (1 ng/mL = 0.0029 μmol = 2.9 mmol\
> specific to methadone molecular weight)

# Appendix 6. MedWatch Form

![](media/image7.png){width="6.330555555555556in"
height="8.105555555555556in"}

# Appendix 7. PedTox Case Report Form (from NAME)

The following case report form is from the Pediatric Toxicology (PedTox)
Registry at the National Association of Medical Examiners (NAME) web
site -- [http://www.thename.org/pedtox_index.htm]{.underline}.

![](media/image8.jpeg){width="6.216666666666667in"
height="5.889583333333333in"}

*Note: The examples for item C under "Role" -- e.g., "fall while
intoxicated, drunk driver" -- do not appear applicable for this
population of children and require reinterpretation by the reporter.*

# Appendix 8. Methadone Identified in Laboratory Testing

**M E M O R A N D U M**

To: Alan Trachtenberg

From: Jane C. Maxwell

Date: April 22, 2003

Subject: Data on Methadone Identified in Laboratory Tests

In preparing for the upcoming Methadone Associated Mortality: A National
Assessment Meeting, I went to the data in the National Forensic
Laboratory Information System (NFLIS) to see what information might be
available on methadone in that dataset. NFLIS, which is sponsored by the
Drug Enforcement Administration, collects results from drug analyses
conducted by State and local forensic laboratories. It reflects drug
evidence seized by law enforcement agencies and analyzed by forensic
laboratories. NFLIS started in 1997 and the number of laboratories
participating in the system in 2002 has grown to 35 State lab systems
and 52 local or municipal labs for a total of 184 individual labs. The
NFLIS system is continuing to grow, as the tables below show.

Table 1 shows the number of items which were examined and identified as
hydrocodone, oxycodone, methadone, and then the total number of all
items identified by NFLIS for 1999-2002 in all labs reporting
nationwide.

  ---------------- -------------- ------------- ------------- -------------
  **Table 1.                                                  
  Number of Items                                             
  Examined and                                                
  Reported to                                                 
  NFLIS\***                                                   

                   **1999**       **2000**      **2001**      **2002**

  Hydrocodone      2,153          4,157         6,665         8,944

  Oxycodone        839            2,799         5,752         8,313

  Methadone        249            461           1,002         2,221

  All Items        437,059        615,165       810,045       927,484
  ---------------- -------------- ------------- ------------- -------------

Table 2 shows the percent increase for each group of drugs year by year.
Notice that while the number of cases is increasing each year, the
difference in growth between years is lessening for hydrocodone and
oxycodone, while the difference is increasing for methadone, which could
mean that methadone is becoming more available and replacing these other
drugs as their availability becomes more restricted.

  -------------------- -- ---------------- ---------------- ----------------
  **Table 2. Percent                                        
  Increase in Items                                         
  Examined and                                              
  Reported to                                               
  NFLIS\***                                                 

                          **1999-2000**    **2000-2001**    **2001-2002**

  Hydrocodone             93%              60%              34%

  Oxycodone               234%             106%             45%

  Methadone               85%              117%             122%

  All Items               41%              32%              14%
  -------------------- -- ---------------- ---------------- ----------------

Table 3 shows the forms of methadone which were identified by the
laboratories reporting to NFLIS. "No form specified" means that when the
data were sent to NFLIS, the field was blank, and most of these items
come from laboratories that do not record this type of information in
their databases. "Unspecified" means the laboratory reported to NFLIS
that the form was unspecified, and these items come from laboratories
that normally record the form of the materials, but for some reason, it
was not specified for these items.

Note that the increase for liquid methadone was only 11 percent from
2001 to 2002, which probably reflects the growth in the NFLIS system,
since the total number of exhibits increased 14 percent in this time
frame. However, the increase in solid tablets was 133 percent, which
could reflect increased availability of the 5mg and 10mg pain pills.

  ------------------------- ---------- ---------- ---------- ---------- ------------- -------
  **Table 3. Form of                                                                  
  Methadone Examined and                                                              
  Reported to NFLIS\*\***                                                             

                            **1999**   **2000**   **2001**   **2002**   **% Change    
                                                                        2001-2002**   

  No Form Specified         111        208        431        662        54%           

  Liquid                    34         70         111        123        11%           

  Other                     2          2          12         28         133%          

  Residue                   5          10         13         40         208%          

  Solid-Powder              3                     21         24         14%           

  Solid-Resin               1                     2          2          0%            

  Solid-Tablet              66         143        325        756        133%          

  Solid-Caplet                                    13         16         23%           

  Solid-Capsule                                   3          2          -33%          

  Solid-Rock                                      1          2          100%          

  Solid-Unspecified         5          7          26         62         138%          

  Unspecified                          5          11         20         82%           

  Unknown                                                    3                        
  ------------------------- ---------- ---------- ---------- ---------- ------------- -------

\*NFLIS "Specific Drug Counts for Methadone" and "25 Most Frequently
Identified Substances" for 1999-2002 downloaded by Jane Maxwell from
NFLIS website, April 21, 2003.

\*\*Email from Albert Bethke to Jane Maxwell, Friday, April 18, 2003.