![](media/image1.jpeg){width="3.920138888888889in" height="0.75in"}

**Acknowledgements**

A number of individuals contributed to the development of the National
Assessment Meeting and this Background Briefing Report. 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:
Background Briefing Report. CSAT Publication No. xx-xx. 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. xx-xx

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 -- for a National Assessment of Methadone-Associated
Mortality in May 2003. In preparation for the National Assessment,
SAMHSA commissioned this Background Briefing Report, which contains
research data and other information to help establish a common
understanding of the problem. The Briefing Report was distributed to
participants in advance of the May meeting.

Participants in the National Assessment carefully reviewed the
information presented in this Background Briefing Report, as well as
data presented at the meeting on methadone formulations, distribution,
patterns of prescribing and dispensing, as well as the relevant data on
drug toxicology and drug-associated morbidity and mortality. They
arrived at a number of important findings regarding the reports of
methadone-associated mortality and formulated recommendations for
reducing that mortality. Their findings and recommendations are
summarized in a Report of the National Assessment, which is available on
SAMHSA's web site and as a print document; participants' slides and
other presentation materials also can be found 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 National Assessment thus 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

Part 1. Purpose of the National Assessment

Part 2. Definitional Issues

Part 3. Recent Concerns About Methadone

Part 4. Pharmacology of Methadone

Part 5. Methadone in Opioid Agonist Therapy

Part 6. Methadone Abuse and Associated Mortality

Part 7. Forensic Issues

Part 8. References and Bibliography

Part 9. Appendices

Appendix A. Epidemiologic Databases Consulted

Appendix B. Past Investigations of Methadone-Associated Mortality

Appendix C. Methadone Serum Level Conversion Factors

Appendix D. MedWatch Form

Appendix E. PedTox Case Report Form (from NAME)

Appendix F. Methadone Identified in Laboratory Testing

**Contents: Conference Papers**

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

**Report of the National Assessment**

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

# 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, which in 2001 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 -- for 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. As a result of their
deliberations, participants arrived at a number of important findings
regarding the reports of methadone-associated mortality and formulated
recommendations for reducing that mortality. Their findings and
recommendations are summarized in a Report of the National Assessment,
which is available on SAMHSA's web site and as a print document;
participants' slides and other presentation materials also can be found
on the web site.

# Part 2. Definitional Issues

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 a 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, or quantity of
methadone implicated in an individual's death often are difficult to
determine. Thus, the identification and classification of
methadone-associated mortality cases may be perceived as encompassing a
complex mosaic of many interacting factors that are variously discussed
in the literature. Some of these critical factors are depicted as a
matrix in ***Table 1***.

This matrix is only a tentative overview of possible factors; more a
point of departure than a finished product. In general, some of the
factors pertain specifically to identifying whether or not methadone
itself is a culpable agent in the death, the extent of its involvement
if any, and how to classify manner and cause of death. Other factors,
such as methadone source and the intention/volition behind its use,
might help to determine preventive measures -- e.g., educational
efforts, closer monitoring of prescribed users -- to avert future
fatalities.

In developing this document, major electronic databases were searched
for resources relating to methadone-associated deaths and the
pharmacology/toxicology of methadone. A significant number of
epidemiologic databases also were identified and are listed in
***Appendix A***. Further case data were gathered from State and Federal
sources, as they became available, and were incorporated for
informational purposes.

<table style="width:100%;">
<colgroup>
<col style="width: 21%" />
<col style="width: 13%" />
<col style="width: 0%" />
<col style="width: 2%" />
<col style="width: 4%" />
<col style="width: 5%" />
<col style="width: 3%" />
<col style="width: 0%" />
<col style="width: 3%" />
<col style="width: 2%" />
<col style="width: 4%" />
<col style="width: 3%" />
<col style="width: 3%" />
<col style="width: 4%" />
<col style="width: 4%" />
<col style="width: 1%" />
<col style="width: 18%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="17"><strong>Table 1: Potential Factors in the
Identification &amp; Classification of<br />
Methadone-Associated Mortality Cases</strong></td>
</tr>
<tr class="even">
<td><strong>Toxicology</strong></td>
<td colspan="7"><strong>Methadone</strong><br />
<em>Dose (mg) - Serum Level (ng/mL)</em></td>
<td colspan="2"><strong>±</strong></td>
<td colspan="7"><strong>Polydrug Involvement</strong><br />
<em>Prescribed - Illicit - Alcohol - Other</em></td>
</tr>
<tr class="odd">
<td><strong>Methadone Source</strong></td>
<td colspan="8"><strong>Licit Prescribing/Dispensing</strong><br />
<em>OTP Clinic<br />
Physician Rx for Analgesia</em></td>
<td colspan="8"><strong>Illicit Diversion/Unauthorized Use<br />
</strong><em>From OTP clinic - Physician Rx - Pharmacy thefts, losses -
Other (“street purchase”)</em></td>
</tr>
<tr class="even">
<td><strong>Methadone Formulation</strong></td>
<td colspan="8"><strong>Oral<br />
</strong><em>Tablet; Disket; Liquid</em></td>
<td colspan="8"><strong>Intravenous Injection<br />
</strong><em>Manufactured Product; Reconstituted<br />
[e.g., crushed tabs]</em></td>
</tr>
<tr class="odd">
<td><strong>Purpose for<br />
Methadone Use<br />
or Abuse<br />
</strong><em>(Intention/Volition)</em></td>
<td colspan="3"><strong>Therapeutic<br />
</strong><em>Maintenance, Opioid Detox,<br />
or Pain Rx</em></td>
<td colspan="5"><strong>Self-Medication<br />
</strong><em>Euphoria, Self-Tx Withdrawal,<br />
Self-Tx Pain</em></td>
<td colspan="5"><strong>Suicide<br />
</strong><em>Intentional Overdose, Self-Inflicted Harm</em></td>
<td colspan="3"><strong>Homicide<br />
</strong><em>Malicious Intent to Harm Another Person</em></td>
</tr>
<tr class="even">
<td><strong>Pharmacologic<br />
Tolerance Level</strong></td>
<td colspan="3"><strong>Opioid Tolerant<br />
</strong><em>Dependence</em></td>
<td colspan="5"><strong>Methadone Tolerant<br />
</strong><em>Dependence</em></td>
<td colspan="5"><strong>Low Tolerance<br />
</strong><em>Occasional Opioid/Methadone Use or Abuse</em></td>
<td colspan="3"><strong>Opioid Naïve<br />
</strong><em>No Tolerance</em></td>
</tr>
<tr class="odd">
<td><p><strong>Methadone Attribution</strong></p>
<p><em>(Several Classification Schemes in Literature)</em></p></td>
<td colspan="16"><p><strong>Primary – Secondary – Concomitant
Suspect</strong></p>
<p><em>Causative – Probable – Possible – Coincidental Agent</em></p>
<p><em>Methadone-Caused – Methadone-Related –
Methadone-Detected</em></p></td>
</tr>
<tr class="even">
<td><strong>Morbidity</strong></td>
<td colspan="8"><strong>Pre-existing Medical or Psychiatric
Condition<br />
</strong><em>(Including Cardiopathology,<br />
Long QT Syndrome)</em></td>
<td colspan="8"><strong><em>De Novo</em> Pathology<br />
Associated with Death<br />
</strong><em>(Including Arrhythmia)</em></td>
</tr>
<tr class="odd">
<td><strong>Manner of Death Classification</strong></td>
<td><strong>Natural</strong></td>
<td colspan="5"><strong>Accidental</strong></td>
<td colspan="5"><strong>Suicide</strong></td>
<td colspan="4"><strong>Homicide</strong></td>
<td><strong>Undetermined</strong></td>
</tr>
<tr class="even">
<td><strong>ICD-9 Code<br />
</strong><em>(International Classification of Diseases [World Health
Organization] –no methadone-specific coding)</em></td>
<td colspan="2"><strong>N965.0</strong><br />
<em>Poisoning by opiates &amp; related narcotics.</em></td>
<td colspan="3"><strong>E850.0</strong><br />
<em>Accidental poisoning by opiates &amp; related narcotics.</em></td>
<td colspan="5"><strong>E950.0</strong><br />
<em>Suicide by analgesics, antipyretics, and antirheumatics.</em></td>
<td colspan="4"><strong>E980.0</strong><br />
<em>Poisoning with undetermined intent by analgesics, antipyretics and
antirheumatics.</em></td>
<td colspan="2"><strong>E935.0</strong><br />
<em>Adverse effect of opiates and related narcotics in therapeutic
use.</em></td>
</tr>
<tr class="odd">
<td><strong>ICD-10 Code<br />
</strong><em>(International Classification of Diseases [WHO] –
methadone-specific coding)</em></td>
<td colspan="4"><strong>X42</strong> <em>and</em>
<strong>T40.3</strong><br />
<em>Accidental poisoning involving methadone.</em></td>
<td colspan="8"><strong>X62</strong> <em>and</em>
<strong>T40.3</strong><br />
<em>Intentional poisoning<br />
involving methadone.</em></td>
<td colspan="4"><p><strong>Y12</strong> <em>and</em>
<strong>T40.3</strong><br />
<em>Poisoning with undetermined intent involving methadone.</em></p>
<p><em>Source ICD 10 Codes:<br />
van Laar et al. 2002</em></p></td>
</tr>
</tbody>
</table>

# Part 3. Recent Concerns About Methadone

Recent press reports of methadone-associated deaths have stirred
widespread concern among policymakers and the public. 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.

Other articles and editorials appeared nationwide with the common theme
that the upsurge in methadone abuse appeared linked to one of three
factors:

-   **First**, there have been ongoing increases in abuse of heroin and
    opioid analgesics and, when other drugs are unavailable, some
    persons are turning to methadone.

```{=html}
<!-- -->
```
-   **Second**, methadone has become more widely available as an
    increasing number of physicians prescribe it for pain relief.

-   **Third**, in at least some States, methadone has become more
    accessible to unauthorized users as opioid treatment programs
    (OTPs), following new Federal regulations, have relaxed their
    policies regarding patients' take-home doses of the drug (Editorial
    2003).

The news articles consistently noted that persons attracted to
unauthorized uses of methadone fall into two categories: (1) those
addicted to other opioids and (2) naïve users who have not previously
used opioids. Most of the articles also acknowledged that methadone
often is abused in combination with other drugs and/or alcohol, and that
its abuse is part of an upward trend in *overall* abuse of opioids,
which has been recognized as a national problem.

Concerns about fatalities associated with methadone are not new, as
extensive surveillance data have documented cases ever since its
implementation as an analgesic and, later, in the treatment of opioid
addiction. This has been against a background of increasing worldwide
drug abuse overall, particularly involving opioid drugs, which are
potent agents with capacities for engendering adverse reactions,
interactions with other agents, and respiratory depression in overdose,
possibly leading to death.

Recent reports from SAMHSA's National Survey on Drug Use and Health
(formerly the National Household Survey on Drug Abuse; 2001, 2002, 2003)
show that the number of new non-medical users of prescription drugs has
increased steadily since the mid-1980s, especially among younger persons
(***Figure 1***). Of particular interest, the number of new non-medical
users of opioid pain medications (top line) consistently and sharply
increased from 400,000 in the mid-1980s to about 2 million in 2000.
These non-medical users are presumed to be abusing drugs primarily for
recreational purposes, leading potentially to overdose and/or addiction
(ONDCP 1999).

![](media/image2.jpeg){width="3.4569444444444444in"
height="2.1319444444444446in"}

**Figure 1**: Annual numbers of new non-medical users of
prescription-type\
drugs, by drug category -- 1965-2000 (NHSDA, SAMHSA 2001).

SAMHSA's latest Drug Abuse Warning Network (DAWN) report noted that the
incidence of emergency department visits related to opioid analgesic
abuse dramatically increased in the U.S. from 1994 and 2001 (SAMHSA
2003; see ***Figure 2***). Nationwide, in 2001 alone, opioid analgesics
were involved in 14 percent of all drug abuse-related emergency
department visits: there were 21,567 hydrocodone-related and 18,409
oxycodone-related emergency department visits, compared with 10,725 for
methadone.

![](media/image3.wmf)

**Figure 2**: Percentage increase in hospital emergency department\
visits associated with opioid analgesics, 1994-2001 (SAMHSA 2002).

In 2001, opioid dependence (presumably equating to addiction rather than
mere physical dependence) was the most frequently mentioned motive for
analgesic abuse, followed by suicide attempts, attraction to psychic
effects of the drugs, and unknown or other motives. The average age of
persons visiting emergency departments for opioid abuse was 37, numbers
of men to women were fairly equivalent, and more than one drug was
involved in 72 percent of cases (SAMHSA 2003).

The data suggest that a significant proportion of methadone-associated
deaths involve opioids either singly or, more commonly, in combination
with other drugs. Male decedents greatly outnumber females and tend to
be older than age 30. There also is an apparent proclivity for opioid
misusers to abuse more than one drug -- such as alcohol, other opioids,
sedatives, or tranquilizers -- which can enhance CNS-depressant effects
of the opioid with potentially fatal outcome. In view of this, it is
important to take into account all drugs forensically detected
postmortem. This presents a challenge for achieving more accurate
forensic determinations of cause of death in these cases, and it
highlights the possible need for appropriate case definitions, as well
as for improved systems of gathering and classifying premortem or other
data for surveillance and prevention purposes (see the discussion at
***Part 7***).

# Part 4. Pharmacology of Methadone

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).

Methadone's 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 make it an appropriate choice
for opioid therapy of pain and addiction (Lobert 2003; Bruera 2002;
Payte et al. 1994; Joseph and Woods 1994; Kreek 1992; Ettinger et al.
1979).

### *Description and Formulations*

Methadone is a synthetic opioid analgesic with multiple actions similar
to those of morphine, the most prominent of which involve the central
nervous system and organs composed of smooth muscle. Its principal
therapeutic applications are for analgesia and detoxification or
maintenance treatment for opioid addiction. The methadone abstinence
syndrome, although qualitatively similar to that of morphine, differs in
that the onset of action is slower, the course is more prolonged, and
the acute symptoms are less severe.

Methadone hydrochloride (3-heptanone,
6-\[dimethyl-amino\]-4,4-diphenyl-, hydrochloride) is a white,
essentially odorless, bitter-tasting powder that is very soluble in
water, isopropanol, and chloroform, and practically insoluble in ether
or glycerin. Methadone has the empirical formula C~21~H~27~NO•HCl and
its molecular weight is 345.91(Mallinckrodt 1995, 2000; Roxane 1995,
1998, 2000). The structural formulas for methadone and its two major
metabolites are depicted in ***Figure 3***. Methadone undergoes
enzymatic *N*-demethylation to form EDDP
(2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine), and subsequent
*N*-demethylation to EMDP (2-ethyl-5-methyl-3,3-diphenylpyraline) --
both of which are inactive metabolites (Moody et al. 1997). Urinary
excretion of methadone and EDDP accounts for 17 to 57 percent of a given
dose, depending on urinary pH, and fecal elimination of methadone and
metabolites is a secondary route (Eap et al. 2002).

![](media/image4.png){width="4.439583333333333in"
height="1.4083333333333334in"}

**Figure 3**: Methadone and its two primary inactive metabolites
(adapted from Moody et al. 1997).

Because of its chemical structure, methadone exists in two enantiomeric
forms having the same chemical composition but different spatial
arrangements, with the enantiomers being mirror images of each other
(***Figure 4***). U.S. manufacturers distribute methadone as a 50:50
racemic mixture of the two enantiomers, specified as "R" (also called
*levo-* or *l-methadone*) and "S" (*dextro-* or *d-methadone*). Only
R-methadone has clinically significant μ-receptor agonist activity,
while the S form is essentially inactive as an opioid agonist (Eap et
al. 1999, 2002). Early investigations found that the active R enantiomer
is metabolized slower and has a lower peak plasma level than S-methadone
during stabilized methadone maintenance (Kreek et al. 1979; Nakamura et
al. 1982).

![](media/image5.png){width="3.4854166666666666in"
height="1.413888888888889in"}

**Figure 4**: Active 'R' and inactive 'S' enantiomers of methadone.

Methadone hydrochloride is distributed in several forms: (1) as a
powder, primarily for hospital formulary use, (2) as an injectable
liquid in multidose vials, and (3) in tablets, diskettes, or premixed
liquid concentrate for oral ingestion (Mallinckrodt 1995, 2000; Roxane
1995, 1998, 2000). The three oral formulations are essentially
equipotent in effect (Gourevitch et al. 1999) and are the forms most
commonly prescribed for outpatient treatment, which also makes them most
subject to diversion and/or misuse. Tablets are supplied in 5 mg (0.0145
mmol) or 10 mg (0.029 mmol) doses, diskets (or diskettes) are 40 mg
(0.116 mmol) dispersible tablets, and liquid concentrates contain 10 mg
methadone per mL of fluid.

Mechanisms of Action

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 may even reflect
external stimuli and environment (Eap et al. 2002, 1988).

### *Pharmacokinetics*

Methadone is up to 80 percent orally bioavailable (compared with 30
percent for morphine). Its elimination half-life averages 24 to 36 hours
at steady state, but may range from as short as 4 hours to as long as 91
hours. Similarly, its rate of clearance from the body can vary by a
factor of almost 100. When used in opioid agonist therapy (OAT) -- at
daily, steady-state oral dosing -- methadone should be present in the
blood at levels sufficient to maintain an asymptomatic state throughout
a 24-hour period, without evidence of opioid overmedication or
withdrawal (Inturrisi and Verebely 1972b; Loimer and Schmid 1992; Payte
and Zweben 1998). Serum methadone level (SML) and its elimination
half-life may be influenced by several factors such as poor absorption,
variable metabolism and protein binding, changes in urinary pH,
concomitant medications, diet, physical condition, patient age or
pregnancy, and even vitamins. Considerable flexibility in dosing is
required to stabilize patients in whom methadone pharmacokinetics may be
affected by so many factors (Eap et al. 2002; Inturrisi and Verebely
1972a; Leavitt et al. 2000).

Measuring systemic levels of methadone via SMLs -- in nanograms per
milliLiter, ng/mL (see ***Appendix C*** for conversion factors) -- can
be a helpful diagnostic aid for achieving adequate dosing in difficult
cases. Typically, the methadone serum level peaks about 2 to 4 hours
after dosing and gradually declines during the remainder of the 24-hour
period to trough level (Inturrisi and Verebely 1972b; Payte and Zweben
1998). Although a strong correlation between methadone dose and trough
plasma concentration (r = 0.82, *P* \< .001) was reported by Wolf et al.
(1991), the relationship may not be linear and there also is a need to
account for a high degree of interindividual variation among patients
and the variable pharmacokinetics of methadone itself (Leavitt et al.
2000).

Other data have also demonstrated a significant relationship between
dose and trough SML; however, at each methadone dose there were patients
with widely differing serum concentrations, including one SML
measurement greater than 1000 ng/mL at a dose of only 120 mg/day
(Okruhlica et al. 2002; see ***Figure 5***). The rate-of-change ratio
between peak and trough SML measures can be a more clinically useful
guide, and it has been suggested that the peak SML occurring at 3 to 4
hours post-dosing should be no more than twice the trough level. This
would provide an optimal peak-to-trough ratio of 2 or less (Payte and
Zweben 1998), which can produce normal peak values exceeding 1000 ng/mL
in adequately dosed patients.

![](media/image6.png){width="2.202777777777778in"
height="2.0555555555555554in"}

**Figure 5**: Methadone dose-to-SML relationships in 69\
methadone-maintained patients (Okruhlica et al. 2002).

In a recent poster presentation, Dorsey (2003) examined both trough
*and* peak SMLs in 37 patients stabilized on methadone maintenance,
further demonstrated high variability at each dose interval. All
patients were receiving ≥110 mg/d of methadone (mean 131 ± 16 mg/d);
however, there was a large variance in trough and peak values, along
with virtually no correlation between methadone dose and either trough
or peak SML (*r* = 0.02 and 0.01, respectively; see ***Figure 6***). For
example, one patient at the low end of the dose range (110 mg/d) had a
trough = 0 ng/mL (undetectable) and peak = 233 ng/mL; meanwhile, a
patient at the highest dose (175 mg/d) had trough and peak values of 0
ng/mL and 180 ng/mL, respectively. The mean peak:trough ratio was 1.6
(95 percent CI: 1.5 - 1.7) and there was a strong linear correlation
between peak and trough SML values in these particular subjects (*r* =
0.89, *p* \< .001). Thus, it appears that individual methadone *dose*
may have poor predictive value for estimating trough *or* peak SML
values; although further research seems warranted to clarify this
proposition and in which circumstances, if any, the trough SML value
might be useful in estimating peak SML.

![](media/image7.wmf){width="3.2444444444444445in"
height="2.2493055555555554in"}

**Figure 6**: Lack of correlation between methadone dose and either
trough or\
peak SMLs in 37 methadone-maintained patients (Dorsey 2003).

Researchers have affirmed the benefit of a 150 to 600 ng/mL *trough*
racemic SML to suppress drug craving and a trough level at or above 400
ng/mL to provide adequate opioid cross-tolerance, making ordinary doses
of other opioids ineffective (non-reinforcing or non-euphorigenic)
during methadone maintenance (Eap et al. 2002; Leavitt et al. 2000).
Today, many practitioners consider a trough SML of 400 ng/mL as adequate
therapy for stabilized methadone maintenance; however, clinical studies
have demonstrated that methadone doses widely ranging from 50 mg/day to
more than 900 mg/day may be necessary to achieve that optimal
steady-state trough serum level (Eap et al. 2000). In a cohort of
difficult-to-treat patients -- with refractory opioid recidivism -- all
of them achieved opioid abstinence once serum levels of *R-methadone*
alone approached 400 ng/mL, which required daily methadone doses greatly
exceeding 100 mg in most patients (Eap et al. 2000). Furthermore,
clinical research has determined that the formulation of oral methadone
-- dispensed as either tablet, disket, or premixed liquid -- does not
differentially affect serum levels (Kreek 1973b; Gourevitch et al.
1999).

Methadone metabolism is largely a function of liver enzyme activity
involving cytochrome P450 isoforms (CYP450 enzymes). Drugs that induce
activity of these enzymes can accelerate methadone metabolism,
abbreviate the duration of its effect, lower the SML, and precipitate
abstinence (withdrawal) syndrome. Conversely, CYP450 inhibitors may slow
methadone metabolism, raise the SML, and extend the duration of its
effects (Kreek et al. 1976; Leavitt et al. 2000; Payte and Zweben 1998).
Several CYP450 isoforms -- CYP3A4, CYP2D6, and to a smaller extent
CYP1A2, and also possibly CYP2C9 and CYP2C19 to a minor degree -- are
involved in methadone metabolism (Brown and Griffiths 2000; Cozza and
Armstrong 2001; Eap et al. 1988, 1999, 2002; Foster et al. 1999). There
are genetic and environmental factors acting on these enzymes, leading
to a high degree of interindividual variation in methadone
pharmacokinetics. Individual differences in the activity of CYP3A4 and
CYP1A2, plus a genetic polymorphism of CYP2D6, help account for wide
variances in methadone metabolism. As a result, in patients taking
exactly the same dose of racemic methadone, corrected for body weight,
concentrations of the active R-enantiomer can vary from 1- to 17-fold
even in the absence of potentially interacting licit and illicit drugs
(Eap et al. 1999, 2002).

*(It should be noted that the research and forensics literature
assessing methadone concentrations reflects determinations that were
made in both blood [plasma]{.underline} and [serum]{.underline} (which
is essentially plasma devoid of fibrinogen and other clotting factors).
This results in significant differences in methadone concentrations.)*

### *Pharmacodynamics*

Methadone's primary site of action is at μ-opioid receptors; however,
R-methadone exhibits much greater affinity at the μ~1~ receptor, which
mediates supraspinal analgesia, and at the μ~2~ receptor mediating
spinal analgesia -- making R-methadone up to 50 times more potent than
the S-methadone enantiomer (Eap et al. 2003). There has been some
speculation that the μ~2~ receptor is most important in mediating
respiratory depression, although this requires further investigation
(Sporer 1999; White and Irvine 1999).

Aside from agonist activity at the μ-opioid receptors, both R- and
S-methadone exert antagonistic activity at the *N*-methyl-*d*-aspartate
(NMDA) receptor (Gorman et al., 1997). This has been observed to
counteract opioid tolerance in experimental models of pain (Davis and
Inturrisi 1999) and may be the basis for reduced opioid escalation seen
in patients treated with methadone, compared with morphine, and may help
to explain methadone's superior analgesic effect (Manfredi et al. 2003).
The NMDA receptor is a target for glutamate, a primary excitatory
neurotransmitter in the brain, although other receptors for glutamate
also exist. Blockade of the NMDA receptor can decrease excitability and
reduce seizure activity, which makes it of interest in developing
therapeutic agents. NMDA receptors also have been implicated to play a
role in heroin, cocaine, alcohol, and nicotine addiction; however, the
interaction of methadone and these other agents with respect to the NMDA
system has not been elaborated at this time. Of further interest,
methadone also inhibits the reuptake of both norepinephrine and
serotonin (Codd et al. 1995), and medications sharing this effect have
been important in treating depression and in the treatment of
neuropathic pain (Manfredi et al. 2003). Methadone's possible adjunctive
anxiolytic and/or antidepressant properties, as well as its potential
for pharmacodynamic toxicity as a result of drug interactions (e.g.,
serotonin syndrome) -- especially when used in higher therapeutic doses
-- have not been elaborated.

### *Pharmacologic Tolerance*

Tolerance to opioid effects results in escalation of opioid dose in
clinical use for analgesia as well as during abuse for euphoric effects.
However, methadone can be toxic to anyone who is not tolerant. A single
day's maintenance dose in a tolerant adult can cause life-threatening
respiratory depression in an adult who is not tolerant, and as little as
10 mg can be fatal in a child (Harding-Pink 1993). Moreover, opioid
tolerance appears to be a complex phenomenon and even experienced users
can be at some risk for toxic effects.

According to White and Irvine (1999), it often is erroneously assumed
that increasing doses of opioids will *not* have adverse effects on
respiratory function because tolerance for the drug's respiratory
depressant effects develops at the same rate as tolerance to its
euphoric and analgesic effects. However, this is not necessarily the
case, and variations in tolerance development across different effects
have been demonstrated in animals and humans. Further, some research has
shown that tolerance to the respiratory depressant effects of methadone
is incomplete; thus, even long-term methadone-maintained patients can be
at risk of opioid-induced respiratory depression if there is an acute
and large increase in serum level. Moreover, some drugs, such as alcohol
and other psychotropic agents, exert their euphoric effects primarily
while the blood level of the agent is *rising* (Kramer 2003). Assuming
this also is the case with methadone, it would explain why
opioid-tolerant users might take extraordinary and/or repeated doses,
perhaps in combination with alcohol or other drugs, to achieve a desired
state of euphoria and accidentally induce severe respiratory depression
in the process.

Opioid tolerance is influenced by changes at receptor sites
(pharmacodynamic tolerance) and in opioid metabolism or distribution
(pharmacokinetic tolerance), as seen in chronic dosing. It also has been
shown that the degree of tolerance can be influenced by environmental
factors, whereby certain cues previously associated with the drug can
markedly enhance tolerance, compared with less tolerance observed when
drug is administered in a novel environment. In short, administration of
opioid in an environment not previously associated with the drug can
foster reduced tolerance and higher risk of overdose (White and Irvine
1999).

As a possible explanation for differential tolerance, White and Irvine
(1999) suggest that the euphoric and respiratory depressant effects of
opioids are mediated by different brain regions. The function of the
limbic and cortical regions, mediating euphoria, may adapt more quickly
and readily to drug effects and are more susceptible to environmental
conditioning factors; whereas, brainstem regions controlling respiration
may be less adaptable. Furthermore, reduced tolerance over time -- such
as, during a period of diminished opioid use or abstinence -- can result
in much greater effect per given dose of opioid if/when opioid use is
resumed. That is, a dose that previously had euphoric effects with
minimal respiratory depression may suddenly produce severe respiratory
impairment. White and Irvine say this indicates that many persons who
die of opioid overdose may have had a period of lower than normal opioid
use and hence a loss of tolerance prior to overdose; however, definitive
information on the relative rate of tolerance loss to the analgesic,
euphoric, and/or respiratory effects of opioids is lacking.

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).

***Dosing, Overdose and Toxicity***

Some patients have reported a degree of "somatic distress" even after 12
months of continuing methadone maintenance. These complaints --
including sweating, constipation, drowsiness, sexual problems, and aches
in bones and joints -- have not hindered patient retention in treatment
(Bell and Zador 2000). Although studies have not correlated methadone
dose or blood levels with the distressing signs and symptoms, they could
denote either methadone under- or over-medication in some cases.

A parenteral dose of 8 to 10 mg of methadone is approximately equivalent
in analgesic effect to 10 mg of morphine, and with single-dose
administration the onset and duration of analgesic action of the two
drugs are similar. The combination of methadone's opioid agonistic
activity, antagonism at the NMDA receptor, and the inhibition of
catecholamine reuptake, either additive or synergistic, may explain why
a substantial number of patients with pain refractory to other measures
achieve selective and effective analgesia with methadone and methadone
only (Manfredi et al. 2003).

When administered orally, methadone is approximately one half as potent
as when given parenterally. Oral administration results in a delay of
the onset, a lowering of the peak serum level, and an increase in the
duration of analgesic effect. Methadone *analgesia* effects peak between
1 and 2 hours and last 3 to 5 hours (Ettinger et al. 1979). The
manufacturer-recommended adult dosage for analgesia is 2.5 mg to 10 mg
every 3 or 4 hours as necessary, although some have suggested that the
higher dose is excessive and potentially lethal until tolerance is
well-established over several days (Ettinger et al. 1979). Dosage is
adjusted according to the severity of the pain and the response of the
patient. Occasionally, it may be necessary to exceed the usual dosage
recommended in cases of exceptionally severe pain or in those patients
who have become tolerant to the analgesic effect of opioids
(Mallinckrodt 1995; Roxane 2000).

Dosing regimens for opioid detoxification or maintenance treatment are
quite different than in pain management. To begin, it is suggested that
an initial single dose of 15 to 20 mg of methadone will often be
sufficient to suppress opioid withdrawal symptoms, although higher doses
may be needed for patients physically dependent on high doses of opioids
(Mallinckrodt 1995, 2001). Federal regulations specify "the initial dose
of methadone shall not exceed 30 milligrams and the total dose for the
first day shall not exceed 40 milligrams, unless the program physician
documents in the patient's record that 40 milligrams did not suppress
opiate abstinence" (Federal Register 2001).

Numerous reports have commented on the increased risk of death in the
early stages of methadone maintenance -- the *induction period* (Bell
and Zador 2000; Caplehorn and Drummer 1999; Clark et al. 1995; Drummer
et al. 1990, 1992; Gardner 1970; Harding-Pink 1991). Death in these
cases usually occurs at home during sleep, many hours after peak
pharmacokinetic blood concentration has occurred, which is in contrast
to the more rapid death typically following IV-methadone overdose (Segal
and Catherman 1974).

The increased death rate during induction is recognized as largely due
to difficulties in assessing the opioid dependence status of new
patients. For example, some individuals who claim to be regular users of
heroin or other opioid drugs may be either occasional users or
opioid-naïve. Occasional opioid use does not engender physical
tolerance; thus, if such individuals are started on a program at doses
in excess of their established tolerance, it can lead to fatal
consequences (Baden 1978; Gardner 1970). Moreover, new opioid users take
longer to clear methadone from their systems, placing them at greater
risk of overdose (Karch and Stepens 2000). Oral methadone doses as low
as 20 mg can be fatal, particularly after several days of treatment,
because of accumulation of drug in blood and tissues (CDHAG 2000).

The risk of death in persons beginning methadone maintenance (in
countries without a 40 mg initial day dose cap) has been calculated as
7-fold higher than their risk prior to entering the OAT program
(Caplehorn and Drummer 1999). This risk is nearly 98 times greater for
new patients than for patients who have safely received methadone for
more than two weeks (Karch and Stephens 2000). Some researchers have
noted that a consistent finding in deaths that occur during the
induction period is the involvement of multiple drugs (Bell and Zador
2000). Risk declines substantially after stabilization on methadone and
reductions in illicit drug use during ongoing participation in an OTP.

A long-standing difficulty has been the diversion or theft of legally
prescribed methadone by unauthorized persons (Cairns et al. 1996;
Williamson et al. 1997), and this is a factor in many fatalities (Zador
and Sunjic 2000). Because of its long half-life and consequent potential
for accumulation, inappropriately used methadone may be more dangerous
than heroin (CDHAG 2000). Recently, concerns have centered on the
diversion or theft of methadone tablets prescribed for pain and their
use for recreational purposes, often by opioid-naïve users.

The primary toxic effect of excessive methadone is respiratory
depression with pulmonary edema and/or aspiration pneumonia
(Harding-Pink 1993). White and Irvine (1999) have postulated that the
effects of exogenous opioids, such as methadone, on respiration include
changes in both tidal volume (the amount inhaled and exhaled with each
breath) and respiratory frequency. Low concentrations of opioids appear
to mainly depress tidal volume, whereas at higher concentrations both
tidal volume and respiratory frequency are affected.

#### *Lethal Interactions With Other Agents*

Long ago, Roizin and colleagues (1972) called attention to the "poison
cocktail" that may result from the ingestion of multiple drugs,
including methadone. It has been recommended that explorations of
potentially lethal drug-drug interactions should include examinations of
altered absorption, distribution, tissue uptake, metabolism, and
excretion, as well as the consideration of possible "toxicodynamic"
(toxic pharmacodynamic) interactions at receptor sites (Borron et al.
2001).

Haberman and colleagues (1995) suggest that pharmacologic interactions
between psychotropic drugs can be *additive*, so that the net effect is
the sum of the substances' individual effects, or *supra-additive*
(synergistic or potentiating) when the combined effects are greater than
additive. For example, it has long been observed that tranquilizers and
hypnotics taken together may potentiate the depressant effects of each
drug and of alcohol, so that the combination can produce fatal toxicity
even at doses that would appear moderate when considered separately
(Roizin et al. 1972). Similarly, alcohol and benzodiazepines often have
been implicated with opioids in drug overdoses. In themselves, alcohol
and benzodiazepines are relatively moderate respiratory depressants, but
when combined with a potent opioid they can augment the opioid's effects
(White and Irvine 1999). In an animal model, Borron et al. (2001) found
that the benzodiazepine flunitrazepam -- which is not approved in the
U.S., but is physiologically similar to and 10 times more potent than
diazepam -- doubled the lethality of methadone but not that of morphine
in treated rats. The authors suggest that alterations of methadone
metabolism by the benzodiazepine, or vice versa, was an insufficient
explanation for this outcome, and that modified effects at binding sites
for each drug may play an important role.

Similarly, alcohol acts as an antagonist at the NMDA receptor and thus
enhances GABA effects by increasing duration of Cl^--^ channel opening
(White and Irvine 1999); accordingly, respiratory depression may be at
least theoretically potentiated by a pharmacodynamic interaction due to
methadone's additive (or, perhaps, synergistic) antagonism of the NMDA
receptor.

#### *Cardiac Effects*

There has been recent interest in methadone's possible role in QTc
prolongation potentially leading to torsade de pointes (TdP). Laboratory
experiments have demonstrated effects of high-concentration methadone on
electrical conduction in various cell and tissue types (Horrigan 1990;
Huidobro 1971; Lee and Berkowitz 1977; Mantelli et al. 1986; Rendig et
al. 1980; Seyler et al. 1983; Wu et al. 1994, 1997a, 1997b). The most
recently reported laboratory evidence suggests that methadone, but not
its metabolite EDDP, blocks cardiac HERG K^+^ currents (Katchman et al.
2002), which have been associated with arrhythmogenic properties in the
clinical setting (Tomargo, 2000). In the study by Katchman and
colleagues, fentanyl and buprenorphine also blocked cardiac HERG K^+^
currents; however, the authors noted that this does not necessarily mean
that these agents or methadone cause arrhythmias, since other factors,
such as the degree of protein-binding in plasma, could have significant
influence on the ability of these opioids to block HERG currents in
vivo. The researchers also commented that 89 percent of plasma methadone
is protein-bound, thereby possibly reducing the in vivo amount of
methadone available to inhibit I~HERG~ to 11 percent (free fraction) and
raising the therapeutic index for methadone approximately 10-fold.

Existing evidence in humans of noteworthy QTc prolongations associated
with oral methadone, and their potential for inducing TdP, has been
primarily limited to case reports (Bittar et al. 2002; Krantz et al.
2002), and factors other than methadone may have played a role in
causing arrhythmias in many of these patients. In the largest case
series (Krantz et al. 2002), 9 of 17 patients developing TdP were
receiving methadone maintenance treatment and 8 were receiving oral
methadone for pain. Approximately 82 percent (14/17) of patients had
known risk factors for arrhythmias, such as hypokalemia, or were
concomitantly taking other drugs that could prolong the QT interval.
Therefore, the authors have cautioned that "Our report should not be
interpreted to suggest that high-dose methadone cannot be used safely."

Prospective clinical investigations in the past have indicated minimal
or no cardiotoxic effects solely attributable to oral methadone used
during OAT at stable doses (Huber et al. 2001; Mathot et al. 2002;
Stimmel et al. 1973). A recent poster presentation by Martell and
associates (2003) reported on cardiac status in 151 methadone maintained
patients at 2 months after enrollment (i.e., following induction) and in
135 patients at a 6-month followup assessment. Statistically significant
mean increases in QTc interval compared with baseline were observed at 2
months (10.6 msec increase; mean 429 ± 22 msec) and 6 months (12.1 msec
increase; mean 430 ± 23 msec). The authors concluded that these QTc
prolongations were modest and of uncertain clinical significance, since
there was no increase greater than 40 msec, or QTc \> 500 msec, or any
TdP incidents. There was limited power in this study to accurately gauge
effects of illicit drugs taken during treatment on cardiac conduction,
plus 47 percent of ECGs were abnormal at baseline, with sinus
bradycardia being most common. Also, the authors did not report on
possible methadone dose or SML effects on the QTc interval, although
doses ranged only up to 150 mg/d in these patients.

There is still the question of whether oral methadone doses
significantly higher than those typically used in many OTPs might
engender cardiac risks. A case series from one large program profiling
12 patients receiving ≥500 mg/d of methadone (mean 812 ± 249 mg/d; range
500 - 1400 mg/d) found that females exhibited higher mean QTc values
than males (460 vs 422 msec), as would be expected; however, the overall
mean QTc interval -- 435 ± 45 msec -- was within acceptable limits
(Leavitt 2001). All patients were taking comedications and many had
physical illness, such as HIV, hepatitis, liver cirrhosis, hypertension,
and diabetes; although, none of the patients exhibited signs or symptoms
of cardiac distress. There was a moderate, but nonsignificant,
correlation between methadone dose and QTc interval (*r* = 0.53; *p* =
0.08). In a larger study by Huber et al. (2001), the dose/QTc
correlation was weak and nonsignificant (*r* = 0.20; *p* = 0.08), and
there were only very weak, nonsignificant associations between QTc
changes and methadone peak or trough plasma levels, with correlation
coefficients ranging from 0.01 to 0.18 (*p* range *=* 0.92 - 0.26).

Potential cardiotoxic effects of methadone in naïve users (i.e., those
without established tolerance) are largely unknown. Cardiac conduction
disturbances putatively associated with methadone abuse by such persons
and leading to death would not be detected at autopsy; however,
preexisting cardiovascular disorders, which are relatively prevalent in
the U.S. population, are sometimes discovered and reported. According to
current estimates, nearly 61 million Americans have cardiovascular
disease, including coronary artery disease (CAD), which is the leading
cause of death in the Western world. There are an estimated 300,000 to
400,000 sudden cardiac deaths each year in the U.S., most of which are
due to ventricular arrhythmias. Further, long QT syndrome (LQTS)
potentially influencing dysrhythmias may be more common than presently
imagined: an investigation at one institution found the prevalence of
LQTS of unknown origin was 7 percent among more than 34,000 patients
undergoing routine ECGs during a six-month period (Kocheril 1997).

Persons who abuse multiple drugs, those on methadone maintenance, and
naïve users of methadone all are part of this larger demographic,
although the risks of each group may be magnified by former and/or
current abuse of illicit drugs or alcohol, particularly cocaine because
of its known cardiotoxic effects (Symanski and Gettes 1993). Further, a
significant proportion of opioid-addicted persons have drug-induced
cardiac abnormalities, including cardiomegaly, infectious endocarditis,
coronary artery abnormalities, acquired valvular disease, primary or
secondary myocardial heart disease, pulmonary-associated heart disease,
and congenital cardiac anomalies.

Illicit drug users and alcoholics also are exposed to a number of
general health risks and infectious diseases and are less likely to
receive regular health care. Also, some persons with suspected
drug-induced LQTS may, in fact, have an underlying genetic
predisposition. The percentage of patients harboring silent,
asymptomatic genetic abnormalities of ion channel structures, and
potentially prone to developing TdP with drugs well-tolerated by most
persons, may be larger than is commonly assumed (Backmund et al. 2001a;
Glauser et al. 1977; Hampton 2003; Hser et al. 2001; Mathot et al. 2002;
Stimmel et al. 1973; Takehana and Izumi 2000).

# Part 5. Methadone in Opioid Agonist Therapy 

Methadone was approved in the United States by the Food and Drug
Administration in 1947 as an analgesic and, by 1950, it was being used
to treat the painful symptoms of withdrawal from opioids, usually heroin
(Payte 1991; Rettig and Yarmolonsky 1995). In 1964, it was discovered
that a continuous, daily maintenance dose of oral methadone offered a
number of beneficial effects, allowing otherwise debilitated
opioid-addicted persons to function more normally (***Table 2***: Bell
and Zador 2000; Dole 1988; Joseph and Appel 1993; Joseph and Woods 1994;
Joseph et al. 2000; Kreek 1992, 1993; Payte and Khuri 1993a; NIH 1997;
Stine et al. 1998 Zweben and Payte 1990).

+-----------------------------------------------------------------------+
| **Table 2: Benefits of Daily\                                         |
| Oral Methadone Maintenance**                                          |
+-----------------------------------------------------------------------+
| -   A stable maintenance dose of methadone does not make the patient  |
|     feel either "high" or somnolent, so the person can socialize,     |
|     work or go to school, and generally carry on a normal life.       |
|                                                                       |
| -   Methadone can be taken orally once daily or in split doses,       |
|     helping to limit exposure to injection-borne diseases like        |
|     hepatitis and HIV.                                                |
|                                                                       |
| -   Methadone's gradual, long-lasting effects eliminate drug hunger   |
|     or craving, unlike the rapid ups and downs of short-acting        |
|     opioids which lead to strong desires for more drug.               |
|                                                                       |
| -   Daily drug-seeking to "feed a habit" becomes unnecessary, and the |
|     euphoria-blocking effect of cross tolerance makes other opioids   |
|     undesirable.                                                      |
|                                                                       |
| -   Once a stable dose is reached, there is little change in          |
|     tolerance to the therapeutic effects of methadone, so it does not |
|     take increasingly more of the medication to achieve the same      |
|     results.                                                          |
|                                                                       |
| -   Methadone has a favorable safety profile, with minimal side       |
|     effects.                                                          |
+-----------------------------------------------------------------------+

Since the mid-1960s, methadone maintenance has been studied more
thoroughly as a modality for the treatment of opioid addiction than any
pharmacotherapy for any addiction, and with uniformly positive results
(Joseph et al. 2000; Newman 2001; NIH 1997; ONDCP 1999; Rettig and
Yarmolonsky 1995). Opioid agonist therapy (OAT) generally is used to
describe the use of methadone to treat addiction in an opioid treatment
program (OTP).

Beginning with only 400 patients in 1968, the number of persons being
treated with methadone in OTPs in U.S. has grown steadily over the years
to more than 200,000 patients in nearly 1,200 registered programs in 45
States (excluding only Montana, Idaho, North Dakota, South Dakota, and
Mississippi, all of which still prohibit OAT), as well as the District
of Columbia, Puerto Rico, and the Virgin Islands (SAMHSA, 2003 data).
However, the number of programs and their patient capacities have not
grown sufficiently to serve the growing numbers of patients who need
treatment. For each patient who receives OAT, up to four or more persons
need treatment but find it unavailable (Federal Register 1999, 2001;
ONDCP 1999, 2000; Payte and Zweben 1998).

As with any dose-dependent medication, an adequate methadone dose has
been found to be critical to therapeutic success, and continued opioid
use or relapse to addiction can be virtually eliminated by proper
methadone-dosing practices. Initial research has shown that 80 to 120
milligrams of methadone per day, on average, is optimal for many
patients (Dole 1988). Such adequate doses result in better treatment
outcomes, as measured by increased retention of patients in treatment
and less illicit drug use.

For several reasons, including physical condition, mental status,
interactions with other medications, or prior use of high purity street
heroin, some patients require significantly greater daily methadone
doses for treatment success -- doses often exceeding 200 mg/day or more
(Gordon 1994; Payte and Khuri 1993a; Stine et al 1998).

At one time, some authorities expected that methadone could be used
simply as an agent to transition patients to drug-free lifestyles,
including eventual withdrawal from methadone itself (NIH 1997; Payte and
Zweben 1998). However, only 54 to 73 percent of patients are able to
successfully complete medically supervised methadone withdrawal
programs, and nearly three-quarters of such patients relapse to drug
abuse within just six months (Backmund et al. 2001). Research has
further demonstrated that virtually all patients who complete a
supervised methadone withdrawal program or otherwise discontinue
methadone, and do not pursue additional and continuing therapy,
eventually relapse to opioid abuse, with correspondingly high mortality
rates (Bell and Zador 2000; Joseph et al 2000; Magura and Rosenblum
2001; Rosenblum et al. 1991; Zanis and Woody 1998).

Based on a review of the research, Bell and Zador (2000) concluded that
methadone maintenance therapy does not necessarily enhance the potential
for eventual abstinence from opioids; however, there are significant
quality of life and health benefits to be gained during methadone
maintenance that overshadow any negative connotations of continued
dependence on opioid medication. For example, mortality from all causes
in methadone-treated patients is typically many-fold lower than in
untreated opioid addicts (NIH 1997), and studies have consistently shown
that the risk of communicable infection is significantly reduced by
participation in opioid treatment, even in patients who cannot achieve
total abstinence from illicit drugs (Leshner 1999; Federal Register
1999, 2001).

An early and large study in New York City that followed 17,500 methadone
maintenance patients from 1965 to 1971 found that the mortality rate
from all causes for persons receiving OAT with methadone was similar to
that for the general population. By contrast, mortality in untreated
heroin addicts was more than 15 times higher (Gearing and Schweitzer
1974). Roizin and colleagues (1972) have reported that the fatality rate
among methadone-maintained patients is between 1 and 1.3 percent, but
increases to 10 percent among those who are discharged from or who
voluntarily discontinue treatment.

Recent epidemiologic studies have supported these early results,
confirming the protective effects of methadone maintenance and
demonstrating that the relative risk of death is three to four times
*lower* for an individual continuing in an OTP compared with one who
discontinues treatment (Bell and Zador 2000; CDHAG 2000).

Deaths occurring during induction into methadone maintenance have been
reduced as physicians have become better educated in prescribing
methadone. An important factor has been the limits placed on the initial
dose (30 mg.) and the first day's dose (40 mg.) by the FDA, and
continued by SAMHSA when it assumed responsibility for regulation of
OTPs in 2001.

# Part 6. Methadone Abuse and Associated Mortality 

Methadone was widely used in clinical medicine as an analgesic and
antitussive long before maintenance therapy for opioid addiction was
introduced in the 1960s. According to a brief review by Harding-Pink
(1993), early indications for methadone included migraine, dysmenorrhea,
labor pain, trigeminal neuralgia, advanced cancer or tuberculosis,
tetanus, and temporary treatment of opioid withdrawal symptoms. Almost
from its earliest use, however, deaths have been associated with
methadone.

During an early clinical trial in the late 1940s, methadone was
implicated in the death of one patient and associated with severe
respiratory depression in another. In the 1950s, several deaths were
reported in England and Germany among young children exposed to
methadone, typically in cough syrups, and other fatalities were reported
in countries where methadone was widely used. Because of its perceived
toxicity and dependence liability, methadone largely fell into disuse by
the early 1960s (Harding-Pink 1993), although there has been renewed and
growing use of methadone as an analgesic in recent years.

With its introduction as maintenance therapy for opioid addiction during
the mid-1960s, methadone regained its place in medical practice.
Worldwide consumption of methadone rose rapidly and exponentially.
However, there also were cases of poisoning associated with methadone in
many cities that instituted OAT programs (Harding-Pink 1993; also see
***Appendix B***).

There also have been sporadic reports of inadvertent poisonings among
the children or family members of methadone-treated patients, especially
when methadone was distributed for take-home use in liquid forms and
packaging that masked its identity to the uninformed (Harding-Pink
1993).

***National Data on Abuse of Methadone and Related Drugs***

Recent reports from SAMHSA's National Survey on Drug Use and Health
(formerly the National Household Survey on Drug Abuse; 2001, 2002, 2003)
show that the number of new non-medical users of prescription drugs has
increased steadily since the mid-1980s, especially among younger persons
(***Figure 7***). Of particular interest, the number of new non-medical
users of opioid pain medications increased from 400,000 in the mid-1980s
to about 2 million in 2000. These non-medical users are presumed to be
abusing drugs primarily for recreational purposes, leading potentially
to overdose and/or addiction (ONDCP 1999).

![](media/image2.jpeg){width="3.4569444444444444in"
height="2.1319444444444446in"}

**Figure 7**: Annual numbers of new non-medical users of
prescription-type\
drugs, by drug category -- 1965-2000 (NHSDA, SAMHSA 2001).

In 2001, opioid dependence was the most frequently mentioned motive for
analgesic abuse, followed by suicide attempts, attraction to psychic
effects of the drugs, and unknown or other motives. The average age of
persons visiting emergency departments for opioid abuse was 37, numbers
of men to women were fairly equivalent, and more than one drug was
involved in 72 percent of cases (SAMHSA 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).

From 1994 to 2001, SAMHSA's Drug Abuse Warning Network (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).

Moreover, SAMHSA's latest Drug Abuse Warning Network (DAWN) report show
that the incidence of emergency department visits related to opioid
analgesic abuse dramatically increased in the U.S. from 1994 and 2001
(SAMHSA 2003; see ***Figure 8***). Nationwide, in 2001 alone, opioid
analgesics were involved in 14 percent of all drug abuse-related
emergency department visits: there were 21,567 hydrocodone-related and
18,409 oxycodone-related emergency department visits, compared with
10,725 for methadone.

![](media/image8.wmf)

**Figure 8**: Percentage increase in hospital emergency department\
visits associated with opioid analgesics, 1994-2001 (SAMHSA 2002).

***National Data on Methadone-Associated Mortality***

Federal data show that a significant proportion of methadone-related
deaths involve opioids either used alone or, more commonly, in
combination with other drugs. Males greatly outnumber females among
decedents, most of whom are older than age 30.

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 (***Figure 9***). These excluded duplicate
reports, deaths in children (including fetuses \[stillborn\] and
infants), and cases from outside the U.S.

![](media/image9.png){width="3.8826388888888888in"
height="2.504166666666667in"}

**Figure 9**: Trends in FDA MedWatch data reporting\
methadone-associated deaths.

It should be noted that the FDA's AERS system relies on voluntary
participation by providers (although reporting is mandatory for events
known to a pharmaceutical company that markets the drug in question) and
only a small proportion of all actual cases are submitted, resulting in
underreporting, typical for a passive surveillance system. For example,
during the early 1970s, Barton (1975) obtained information on
methadone-associated deaths by contacting medical examiners and coroners
across the U.S. He found that, for 25 areas of the country providing
usable data, there were 156 deaths involving methadone in 1971 and 332
such deaths in 1972 -- a 113 percent increase, possibly due to rapid
growth in under-regulated methadone programs during that time. In the
FDA data noted above, there were only two cases in 1971 and six cases in
1972 reported via the MedWatch system. Still, AERS data represent a
large and long-running passive surveillance system that yields a number
of case reports; it is possible that observed trends may be more
important than actual numbers of reports for each year.

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 rather than, or in addition to,
methadone (Litovitz et al. 2002; Fingerhut and Cox 1998; Cone et al.
2003; Eastwood 1998). This continues a trend that has been developing
over a number of years. As shown in ***Figure 10***, virtually all
increases in poisoning deaths between 1985 and 1995 involved drugs, with
the death rate in males for that category nearly tripling (from
5.5/100,000 population to 16.1/100,000) and the rate for females
increasing 60 percent (to 6.0/100,000). In particular, the male death
rate associated specifically with opioids (ICD-9 codes E850 and 305.5)
increased more than three-fold, from 1.1 to 3.5 per 100,000, and
comparable rates for females also increased but less dramatically so
(Fingerhut and Cox, 1998).

![](media/image10.png){width="4.566666666666666in"
height="2.7263888888888888in"}

**Figure 10**: Poisoning death rates for males and females\
ages 35-54 during 1985-1995 (Fingerhut and Cox, 1998).

Poison control center data for 2001 (Litovitz et al. 2002) show that 1.7
percent of all reported poison exposure cases in the U.S. (approximately
39,000) were related to intentional drug abuse; that is, resulting from
the intentional improper use of a substance where the victim likely was
attempting to achieve a euphoric or psychotropic effect. Of 1,074
fatalities reported by poison control centers, 144 resulted from
intentional substance abuse, most commonly involving opioid analgesics,
followed by sedative/hypnotics, antidepressants, and "street"
drugs/stimulants. However, such poison control center reports are known
to underreport drug-related fatalities. Considering all causes (i.e.,
intentional and otherwise), oxycodone products were implicated in 54
deaths and hydrocodone products in 47. Most notably, there was a sharp
increase in long-acting oxycodone product deaths, from 8 in 2000 to 21
in 2001, with roughly half (11/21) involving polysubstance abuse. Nearly
2,000 methadone exposures were reported to poison control centers in
2001 (including 1,109 intentional abuse cases) resulting in 36 deaths
overall; however, multiple substances were involved in 15 of 23 (65
percent) of fatal methadone cases that were summarized in detail.

Three primary scenarios are seen in methadone-associated deaths:

1\. Accumulations to toxic levels during the start of opioid
detoxification or beginning methadone maintenance treatment (i.e., the
induction period prior to methadone steady-state and tolerance
development) or in pain management with legitimately dispensed
methadone;

2.  Misuse of diverted methadone by essentially opioid naïve persons or
    by those who have diminished opioid tolerance; who also may take
    excessive and/or repetitive doses in an attempt to achieve euphoric
    effects;

3.  Additive or synergistic effects of other CNS-depressant agents --
    e.g., benzodiazepines, alcohol, heroin or other opioids -- taken in
    conjunction with methadone (primarily taken for abuse) by either
    opioid-naïve or opioid-tolerant individuals, although the amounts
    fostering toxicity and death would vary across individuals.

Research suggests that methadone dose amounts and blood concentrations
do not necessarily predict outcome. Further, isolated postmortem serum
concentrations of methadone do not appear to reliably discriminate
between victims who have died from methadone toxicity and cases in which
the presence of methadone is purely coincidental. This presents a
challenge for achieving more accurate forensic determinations of cause
of death in these cases, and it highlights the possible need for
appropriate case definitions, as well as for improved systems of
gathering and classifying premortem or other data for surveillance and
prevention purposes.

Currently available data do not implicate OTPs as a significant source
of methadone in fatality cases. In the instances in which the exact
source was known and reported, methadone originated from OTPs
infrequently; whereas solid forms (tablets), primarily prescribed for
pain and distributed through pharmacies or hospitals, appeared to be a
more common source of methadone associated with deaths. Methadone
dispensed by OTPs is almost entirely in the liquid form, although the
new regulations (42 CFR 8) did, for the first time in 2001, allow for
the use of solid methadone in OTPs. Liquid methadone is rarely used for
outpatient pain control.

Morever, while reports of methadone-associated fatalities have increased
during recent years, epidemiologic data strongly suggest that these
incidents were on the rise *prior to* the institution, in 2001, of
revised Federal regulations governing OAT programs that liberalized
methadone dispensing and take-home allowances for stabilized patients
(Federal Register 2001, 42 CFR Part 8).

Additionally, the new provisions in the regulations have been adopted at
a very slow pace. For example, in Florida, less than one percent of all
patients in methadone treatment are receiving take-home methadone at
intervals greater than once every 14 days (Phil Emenheiser, Florida
State Methadone Authority, personal communication, March 2003). At the
same time, there has been a renewed awareness in the medical community
of methadone's value as an analgesic, with a corresponding increase in
its use and potential for diversion, misuse, or even iatrogenic
overdose. This has coincided with increases in the prescribing of *all*
opioid-analgesics as physicians have become more sensitive to providing
adequate and effective pain management for patients who need it.
Therefore, methadone's expanded distribution, availability, and
consequent reports of misuse (and associated deaths) must be considered
within the context of increased availability of methadone for analgesic
purposes, as well as growing abuse of *all* opioid medications.

State Data on Methadone Abuse and Associated Mortality

At the state level, concerns have been sparked by local 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). The data suggest a correlation between increased pharmacy
distribution of methadone tablets for pain management and increased
problems with methadone, including methadone-associated deaths.

**Maine.** In Maine, surveillance data depict an increase in
methadone-associated fatalities that roughly paralleled the increase in
all drug deaths between 1997 and 2002 (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).

The rate of overall accidental drug-overdose deaths in Maine, as well as
the rate attributable to methadone, rose significantly during 2000 and
2001, and both were expected to increase again during 2002 (***Figure
11***). Methadone-caused and methadone-related deaths, together,
constituted nearly one-third (31 percent) of Maine's 248 accidental
poisoning deaths during 1997-2002 (projected) in a State with a
population of only 1.2 million (Sorg 2002).

![](media/image11.wmf){width="3.438888888888889in"
height="2.5236111111111112in"}

**Figure 11**: Accidental overdose deaths in Maine, 1997-June 2002\
(Sorg 2002).

Drug-related deaths increased statewide, but were concentrated in
Cumberland County, which includes Portland and is one of the most
populous of the 16 counties in the State. From January through June
2002, there were 10 methadone-caused and 4 methadone-related deaths in
Cumberland County, as defined by medical examiners, with another 26
total cases projected for the remainder of 2002. About half of the
deaths were in Portland. However, only a small proportion of decedents
were receiving methadone from OAT clinics or by prescription from
pharmacies for pain (Sorg 2002). In a preliminary analysis of 23
methadone-related deaths from Cumberland County in 2001 and 2002, only 3
(13 percent) decedents were in OTPs, while 2 others (9 percent) had
methadone prescriptions for pain (Sorg and Greenwald 2002), and the
remaining 18 obtained methadone via unspecified sources.

From 1997 through June 2002, the trend in methadone-associated overdoses
roughly paralleled cases of non-methadone-associated drug deaths, except
for an upsurge in 2000 (***Figure 12***). During the entire period,
there were 77 confirmed methadone-associated deaths in which methadone
toxicity was either classified as a primary or underlying cause (N=52,
68 percent) or listed as a significant factor or as one agent in an
undifferentiated mixed-drug-caused case (N=25) (Sorg 2002). Deaths with
methadone identified in their toxicology doubled between 1999 and 2000,
with a leveling in 2001, and the total for 2002 was projected to be more
than double that of 2001 (Sorg and Greenwald 2002).

![](media/image12.wmf){width="4.2in" height="2.3777777777777778in"}

**Figure 12**: Accidental overdose trends comparing methadone (bottom
line)\
and non-methadone (top line) deaths during 1997-2002 in Maine (Sorg
2002).

Opioid analgesics were prevalent in a majority of drug-associated deaths
in Maine, with one or more opioids present in 71 percent of decedents
and identified as a cause of death in 53 percent of those cases.
Overall, the top two opioid drugs were methadone and heroin/morphine,
followed by oxycodone (***Figure 13***). The most frequently occurring
opioid drug combinations were heroin-codeine, methadone-oxycodone, and
heroin-methadone. However, alcohol also was commonly associated with
opioid and non-opioid deaths (Sorg and Greenwald 2002).

![](media/image13.png){width="3.4166666666666665in"
height="2.4722222222222223in"}

**Figure 13**: Number of cases in which key drugs were identified in
Maine\
cases, based on toxicology, 1997-2002 (Sorg and Greenwald 2002).

A detailed examination of 23 methadone-associated death case
descriptions from Cumberland County reveals a number of important
comorbid factors that might have contributed to the risk of overdose
fatality (see ***Figure 14***; Sorg 2002). There appeared to be
significant proportions of underlying conditions, both physical and
mental, along with concomitant medication/drug use among the decedents.
Sorg and Greenwald (2002) commented that, overall, there was a high
prevalence of mental illness and physical conditions (such as, heart,
lung, and liver disease, as well as obesity) associated with drug deaths
in Maine. Many of the physical conditions might diminish respiratory
capacity or otherwise affect the body's ability to maintain homeostasis
under pharmaceutical stress. Adverse reactions associated with
legitimate medications or illicit drugs, on their own or via interaction
with methadone, also might have played a role in mortality. This
exemplifies the many factors that may be important in accurately
attributing cause of death.

![](media/image14.wmf){width="3.798611111111111in"
height="2.165277777777778in"}

**Figure 14**: Examination of 23 methadone-associated death cases in\
Cumberland County, Maine (data from Sorg 2002).

**Florida.** 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 November 2002, the Florida Department of Law Enforcement (FDLE)
issued a report on 2,657 toxicology investigations from the Medical
Examiners Commission, covering January through June 2002 and
representing 3.0 percent of the total 87,500 deaths in the State during
that 6-month period (FDLE 2002). A variety of drugs were noted, with
increased prevalence of *both* lethal and non-lethal levels (in
undefined amounts) noted for benzodiazepines (2 percent), cocaine (4
percent), oxycodone (7 percent), hydrocodone (19 percent), and methadone
(31 percent), compared with the prior 6-month period. Heroin-related
deaths declined 15 percent in the same period.

Significantly, in examining only lethal cases, methadone was the only
agent that showed an increased prevalence (36 percent) from
July-December 2001 to January-June 2002. Of the 254 statewide
methadone-associated deaths during the first six months of 2002, nearly
three-quarters (73 percent) were classified as accidental. Approximately
17 percent were with methadone as the sole agent and 83 percent were in
combination with other drugs; however, determinations of methadone as a
causative agent versus merely "present" were somewhat equivalent (see
***Table 3***). Suspected sources of methadone were not reported.

  --------------------------- -------------- -------------- --------------
  **Table 3: Florida                                        
  Methadone Deaths\                                         
  January - June 2002**                                     

                              **Cause**      **Present**    **Total**

  **Methadone Only**          **23**         **21**         **44**

  **Methadone+Others**        **110**        **100**        **210**

  **Total**                   **133**        **121**        **254**
  --------------------------- -------------- -------------- --------------

**North Carolina.** 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. 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 2002).

The number of deaths attributed to methadone as a *sole agent* increased
more than eight-fold during the five-year period, from 7 in 1997 to 58
in 2001, or from 6 percent to 26 percent of all single agent deaths
during those years (see ***Figure 15***). There also was an increase
during 1999 to 2001 for methadone named as a component of multidrug
deaths.

**Figure 15.**

**Texas.** 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. 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.

**Maryland.** Overall alcohol and drug-related overdose deaths in
Maryland increased 16 percent between 1997 and 2001 (Lehder et al.
2002). The majority of overdoses each year were increasingly accounted
for by single-drug exposures, with two-thirds of cases in 2001
attributable to such causes. The most common type of overdose either
alone or in combination with another drug was broadly classified as
"narcotic-related" (e.g., heroin, but not otherwise delineated).

For single-drug mentions, deaths associated with alcohol or cocaine were
relatively few compared with "narcotics." Methadone-only deaths were
tracked as a separate category and, although small in number, there was
a notable escalation in methadone overdose deaths from 2 in 1997 to 21
in 2001, with the greatest increase from 5 to 14 methadone cases between
1999 and 2000 (***Figure 16***).

![](media/image15.png){width="4.240972222222222in"
height="2.498611111111111in"}

**Figure 16**: Number of single-drug overdose deaths by year\
in Maryland (Lehder et al. 2002).

Total overdose deaths increased 16 percent during the 5-year period
(from 482 to 559), while the proportion of single-drug methadone-related
deaths rose 10-fold from 0.4 to 4.0 percent of the totals. Influences
behind the increases in methadone cases, such as source of the drug,
were undetermined due to insufficient information.

During the 5-year period, males outnumbered females in overdose deaths,
although numbers of females were increasing; for example, rising from 14
percent of the total in 1997 to 21 percent in 2001. The highest
proportion of deaths were in persons aged 31 to 50. Baltimore City and
Central Maryland regions accounted for about 80 percent of all deaths
each year, although every region in Maryland had at least one overdose
per year.

# Part 7. Forensic Issues 

There has been concern among medical examiners and others that faulty
criteria used to attribute cause of death to methadone may artificially
inflate statistics and impede the ongoing development of OAT as a
treatment modality (Merrill et al. 1996). For example, Roizin and
colleagues (1972) have observed that evaluations of toxic drug
interactions can be problematic during autopsy, and that "correlation is
not synonymous with explanation"; that is, the mere presence of multiple
drugs does not necessarily denote their interaction. Difficulties
encountered in retrospectively evaluating drug interactions include (1)
inadequate information about drug dosage, health status and pre-existing
tolerance (medicobiological condition) of the subject; (2) the number of
drugs taken; (3) uncertainties about drug identification and the
temporal relationship between intake and adverse reactions; (4) the
presence of inborn or acquired factors that are facilitating or
predisposing; and (5) the body's limited means of adaptation to adverse
drug effects.

***Postmortem Blood/Tissue Analyses***

Serum methadone levels (SMLs) considered as therapeutic during OAT
commonly overlap those reported in methadone-associated deaths (Milroy
and Forrest 2000; Sorg 2002). In review articles, methadone postmortem
concentrations observed as fatal by various authors have ranged from 60
to 4,500 ng/mL (Mikolaenko et al. 2002; Wolff 2002; also see ***Appendix
C*** for factors used in converting reported measures to ng/mL). In one
study, Caplan et al. (1983) reported several overlapping methadone
concentration ranges found post-mortem: 70 to 1,400 ng/mL in
methadone-only deaths (n=18); 100 to 1,400 ng/mL in polydrug-related
deaths with methadone as one agent (n=16), and 50 to 3,400 ng/mL in
non-drug-related deaths that found methadone present (n=43). While some
pathologists regard an SML greater than 400 ng/mL sufficient to cause
death, even in persons tolerant to opioids (Merrill et al. 1996), this
is at odds with established recommendations for effective OAT, in which
SMLs should be kept within a trough range of 150-600 ng/mL or optimally
at about 400 ng/mL for most patients, with peak levels being two-fold
greater. In view of the high degree of overlap between therapeutic and
putatively fatal methadone serum levels, Segal and Catherman (1974) long
ago questioned whether "overdose" was a properly descriptive term in
association with fatalities and proposed "adverse reaction to narcotic
drugs" as a substitute unless more precise pathophysiologic mechanisms
could be determined and specified. More recently, it was noted that
ascribing death to overdose of a particular drug also detracts attention
from the possible contribution of other drugs to the cause of death
(Zador et al. 1996).

Several factors may affect methadone ranges found in fatalities: low or
lost opioid tolerance; slower or altered opioid metabolism; interactions
with other drugs; and even antibodies to methadone in certain persons.
Furthermore, it would be necessary to consider time of death in relation
to oral ingestion (peak levels expected at 2-4 hours) and the
possibility of postmortem redistribution of methadone (Karch and
Stephens 2000; Sorg 2002; Wolff 2002). Milroy and Forrest (2000)
analyzed 111 fatalities in which methadone was mentioned, with methadone
poisoning given as sole cause of death in 55 cases. Average methadone
concentration in these deaths was 584 ng/mL (range 84-2700 ng/mL) in
whole blood; similarly, mean concentration in 56 cases ascribed to
methadone in combination with other drugs was 576 ng/mL (range 49-2440
ng/mL) in whole blood. However, they note that the ratio of plasma to
whole blood in antemortem samples is 1:1.3, and applying this conversion
factor to postmortem whole blood samples would result in about 23
percent lower *serum level* values prior to death, which underscores the
difficulties of attempting to interpret the lethality of postmortem drug
concentrations in whole blood using parameters of acceptable serum
levels in the living. Of further importance, when multisite blood
sampling was performed by these researchers, there was up to a 100
percent discrepancy in concentrations of methadone, and other drugs,
taken from different sites in the same body. These and other authors
(Karch and Stephens 2000; Prouty and Anderson 1990) have noted that a
degree of caution must be exercised in determining fatal drug
concentrations due to the phenomenon of postmortem redistribution.

Postmortem movement of methadone from other tissues (e.g., liver,
stomach) into blood, and vice versa, may contribute to the problem of
determining accurate concentrations of methadone relative to the cause
of death. Concentrations of drugs in postmortem blood specimens often
increase with time postmortem (Prouty and Anderson 1990).
Site-dependence is another confounding factor: for example, high
quantities of methadone in stomach contents would indicate oral
ingestion; whereas, trace or no evidence in the stomach and high serum
concentrations in blood might suggest other routes of administration
(Milroy and Forrest 2000; Robinson and Williams 1971). Further, Drasch
and colleagues (2000) noted a marked increase of the R-methadone
enantiomer in fatal cases, suggesting selectively and detrimentally slow
metabolism of this component in certain persons or circumstances. Drasch
and colleagues, as well as Karch and Stephens (2000), have proposed the
possible need for enantioselective quantification of methadone
postmortem to achieve greater forensic accuracy.

Finally, in persons engaging in polydrug abuse, methadone itself may not
be sufficient to cause death; however, additive or potentiating effects
of other drugs may increase methadone's lethality. Therefore, some have
argued, *all* significantly measurable drugs should be included in the
cause of death investigation (Milroy and Forrest 2000).

***Death Classification Schemes***

Defining methadone-associated deaths is complicated by problems of
inconsistency among forensic authorities in determining and recording
information surrounding the fatalities. This is further burdened by the
complexity of classification schemes that are subject to interpretation
or vaguely elaborated to begin with, as in many of the epidemiological
reports. At the least, a suitable case definition would involve a
multifaceted approach taking into account a matrix of factors (as shown
in ***Table 1,*** above). Factors critical for prevention would include
the form of methadone (solid versus liquid) ingested and its source
(legitimate or illegitimate); although, the difficulties in making such
determinations must be recognized and overcome.

Currently, the reporting and classification of deaths involving drugs in
the U.S. is closely tied into the death registration system (Fingerhut
and Cox 1998; Hanzlick 1997). All States have a standard death
certificate based on a model form called the "U.S. Standard Certificate
of Death." A manner-of-death classification and cause-of-death section,
which also includes details about the circumstances surrounding death,
are completed by the certifier of death, whether a physician, medical
examiner, or coroner (Hanzlick et al. 2002). Cause and manner of death
are essentially opinions, requiring the educated and informed judgment
of the certifier but supported by substantive evidence. There are five
options in most States for manner-of-death classification: (1) natural,
(2) accidental, (3) suicide, (4) homicide, and (5) undetermined (or
"could not be determined"). This scheme was an American invention, added
in 1910 to death certificates, for helping to clarify the circumstances
of death and further assist in coding cause-of-death information; it is
not addressed directly by World Health Organization classifications
(Hanzlick et al. 2002). Most opioid poisoning or overdose deaths might
be classified as accidental, unless there was evidence of *intent* to
harm oneself (suicide) or another person (homicide). However, there are
many gray areas of interpretation, such as determining whether a drug
exposure was acute (suggesting an accident) or more chronic (possibly
connoting death due to nature causes, even if there was recent drug
abuse).

*Intentionality* -- the motivation or purpose behind drug use -- also is
difficult to determine; for example, was a person taking excessive
amounts of opioid medication attempting to achieve euphoric effects,
quell an acute exacerbation of pain, or commit suicide? As a further
consideration, one author noted that it is difficult to analyze
mortality by a specific drug or even drug class when using death
certificate information, since many cases fall into "other, mixed, or
unspecified" drug categories. (Kallan 1998).

Death certificate information is passed from local authorities to the
State, and from the States to the national level. The U.S. follows World
Health Organization procedures for documenting death, and the coding of
causes is usually done at the State level following the latest version
of the International Classification of Diseases (currently ICD-10 \[NCHS
2002; van Laar et al. 2002\]). These data is submitted to the custodian
of U.S. mortality data, which is the National Center for Health
Statistics (NCHS) within the Centers for Disease Control and Prevention
(CDC). Annual national mortality data reports usually lag about two
years behind the current calendar year (Hanzlick 1997).

Up to 20 causes of death, if reported, can be coded from a single death
certificate (Fingerhut and Cox 1998), so the need for death certifiers
to supply complete and accurate information and for nosologists to be
meticulous in their coding is apparent. However, Hanzlick (1997) has
noted that causes of death are sometimes reported nonspecifically or
incompletely, and even yes/no questions on death certificates -- e.g.,
"Was an autopsy performed?" -- have been inaccurately reported.

The 9^th^ Edition of the International Classification of Diseases
(ICD-9; WHO, 1979) is the version used from 1979 until fairly recently,
with 10^th^ Edition (ICD-10) finding use during 1999-2000 in most
countries. The ICD-9 contains two sets of codes for classifying
poisoning deaths: external cause of death (E-codes) and diagnosis codes.
E-codes, of which there are 114, specify both the intent (e.g.,
unintentional, suicide, homicide) and the drug-class causing the
poisoning: for example, unintentional poisoning by opiates and related
narcotics. Diagnosis codes are used to add specificity to the cause,
also naming a specific agent, but never used to code the underlying
intent of death (Fingerhut and Cox 1998). ICD-10 adopted an alphanumeric
system, so codes differ from those in ICD-9, and blocks of codes
identify deaths due to drug dependence, non-dependent substance abuse,
and accidental, suicidal/self-inflicted, homicidal, and "undetermined
intent" poisoning. The most frequently abused drugs are grouped
together, rather than by therapeutic class, and secondary codes allow
each substance to be further identified. Methadone, which was not
specifically categorized in ICD-9, was specifically added to ICD-10
(Flanagan and Rooney 2002; van Laar et al. 2002). As can be imagined,
with so many classification codes, which must be based on the limited
information provided in death certificates -- and also subject to human
errors in completeness, interpretation, coding, or keying -- there is a
high potential for inconsistencies, inaccuracies, and some confusion
(Kung et al. 2001).

Numerous studies of methadone-associated mortality have gone beyond
death certificate information to include meticulous surveys and
examinations of decedents' medical treatment records and/or
death-certifier investigations (such as, autopsy and toxicology
reports). Some of these studies are listed in ***Appendix B***.
Unfortunately, comparisons of studies are hampered by a lack of common
terminology and case definitions. Some authors have made the semantic
distinction that methadone-*associated* deaths are cases in which
methadone is present but not causative; whereas, methadone-*related*
deaths are those in which methadone contributes directly to the death
process in some way (CDHAG 2000). One researcher proposed a three-tiered
hierarchy of fatalities involving methadone, distinguishing between: (1)
*methadone detected* -- in which methadone is found at autopsy
irrespective of cause of death; (2) *methadone related* -- in which
methadone is detected and cause of death also is found to be
drug-related; c) *methadone caused* -- in which methadone is the sole
agent in a drug-related death (Zador in CDHAG 2000, p 29). However,
causation in this scheme could be erroneously attributed, since many
other factors might play more pivotal roles and methadone's influence
could be entirely benign even as a sole agent. Hence, these subtleties
of definition appear unhelpful, unless the terms are more fully defined
and universally understood and accepted by nosologists.

Cone et al. (2003) recently proposed a different scheme for reporting
and evaluating drug-associated mortality data. Their objective was to
more carefully determine the roles of oxycodone and the specific drug
product OxyContin® in deaths from 1999 to 2002. They found that most of
the evaluated deaths involving the two drugs (90.6 percent) were related
to drug abuse and that the vast majority (96.7 percent) were associated
with the ingestion of multiple drugs, thus highlighting the need to
consider the influence of polydrug abuse when determining cause of death
and to avoid prematurely attributing culpability to any one agent. Only
30 of 919 drug abuse deaths involved oxycodone alone, and only 40
percent of those (12/30) specifically involved OxyContin.

Cone and colleagues developed their categorization scheme using
terminology from SAMHSA's Drug Abuse Warning Network (DAWN). Thus, "drug
abuse" is defined as the non-medical use of a substance for psychic
effect, dependence, or suicide attempt. "Drug-induced death" is a
fatality resulting directly from drug abuse, such as drug overdose or
the interactive effects of drug combinations. "Drug-related death" is a
fatality in which abuse of a drug (or drugs) is a contributing factor,
but is not the sole cause of death. Fatalities are further delineated as
involving either a single drug or multiple drugs. Using these
definitions, the researchers disaggregated mortality cases into one of
11 groups for analysis (***Figure 17***). This particular study was
complicated by the investigators' goal of specifically assessing the
possible involvement of the OxyContin product -- distinguishing it from
oxycodone in general -- and by the fact that their analysis included the
tracking of demographic data and each of the other drugs involved in
multidrug cases. Of interest, methadone was ranked 18th among the top 20
co-abused drugs, being mentioned in about 6 percent (52/889) of
fatalities involving multiple drugs, yet it comprised only 0.7 percent
of U.S. analgesic prescriptions in 2001, according to the authors (based
on IMS data). This might suggest that most of the methadone found in
these individuals was diverted, but further investigation is required.
Cone and colleagues concluded that the use of standardized terminology
and a group classification scheme, such as the one based on the DAWN
system, would enhance future evaluations of opioid involvement in drug
abuse deaths and allow for more meaningful comparisons across studies.

![](media/image16.png){width="3.4381944444444446in" height="5.025in"}

**Figure 17**: Scheme for evaluating oxycodone/OxyContin fatalities
(Cone et al. 2003).

A long-established approach for tracking medication-associated problems
and deaths in the U.S. is ***MedWatch***, the FDA's Safety Information
and Adverse Event Reporting Program. This is a voluntary reporting
system for gathering clinical information about all safety issues
involving medical products, including prescription and over-the-counter
drugs, biologics, and special nutritional products. MedWatch allows
manufacturers, healthcare professionals, and consumers to report serious
problems (including deaths) that they suspect are associated with the
drugs and medical devices they make, prescribe, dispense, or use.

Reporting typically is done by mail or fax, using the multipurpose
MedWatch 3500 form (see ***Appendix D***). The system relies on the
reporter's ability to gather accurate and comprehensive information and
his or her expertise in attributing the event to the drug(s) or
product(s) in question.

Another voluntary reporting system for gathering and evaluating data on
deaths attributed to toxicity and/or poisoning is the Pediatric
Toxicology (PedTox) Registry^®^ sponsored by the National Association of
Medical Examiners (NAME) (***Appendix E***). This focuses on children
age 12 and under (including infants) who were determined to have died
from the toxic effects of a drug or poison. A relatively simple
reporting form is used for submitting data to a designated custodian. In
addition to standard death certificate entries on manner and cause of
death, several other practical areas of useful information are probed,
including demographics. Five categories are used to depict the suspected
*role* of the involved agent(s) to help assess causality. The
accumulated data are evaluated and reported in two sections -- a case
description database and summaries by substance -- which are accessible
at the NAME web site
([http://www.thename.org/pedtox_index.htm]{.underline}) by registered
members. Although this approach targets a specific age group and is
broad-based in terms of the agents of interest, the model appears useful
for gathering qualitative and quantitative intelligence data on
fatalities involving particular substances.

# Part 8. 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 9. Appendices

Appendix A. Epidemiologic Databases Consulted

Appendix B. Past Investigations of Methadone-Associated Mortality

Appendix C. Methadone Serum Level Conversion Factors

Appendix D. MedWatch Form

Appendix E. PedTox Case Report Form (from NAME)

Appendix F. Methadone Identified in Laboratory Testing

# Appendix A. Epidemiologic Databases Consulted

+-----------+----------------------------------------------------------+
| **        |                                                          |
| Databases |                                                          |
| C         |                                                          |
| ontaining |                                                          |
| In        |                                                          |
| formation |                                                          |
| Relevant  |                                                          |
| to Opioid |                                                          |
| Pre       |                                                          |
| scribing, |                                                          |
| Use,      |                                                          |
| Abuse,    |                                                          |
| Ov        |                                                          |
| erdose/Po |                                                          |
| isonings, |                                                          |
| and       |                                                          |
| Fat       |                                                          |
| alities** |                                                          |
|           |                                                          |
| *(Web     |                                                          |
| site URLs |                                                          |
| indicated |                                                          |
| where     |                                                          |
| av        |                                                          |
| ailable)* |                                                          |
+===========+==========================================================+
| **        | 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. OAS is |
|           | responsible for the following major data collection      |
|           | systems that provide this information.\                  |
|           | 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**  | 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** | 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 are       |
|           | 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** | Automation of Reports and Consolidated Orders System     |
|           | (ARCOS) from the DEA. The Controlled Substances Act of   |
|           | 1970 (§ 827) created the requirement for Manufacturers   |
|           | and Distributors to report their controlled substances   |
|           | transactions to the Attorney General. The Attorney       |
|           | General delegates this authority to the Drug Enforcement |
|           | Administration (DEA).                                    |
|           |                                                          |
|           | ARCOS is an automated, comprehensive drug reporting      |
|           | system which monitors the flow of DEA controlled         |
|           | substances from their point of manufacture through       |
|           | commercial distribution channels to point of sale or     |
|           | distribution at the dispensing/retail level --           |
|           | 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** | 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.    |
+-----------+----------------------------------------------------------+
| **        | White House Office of National Drug Control Policy       |
| *ONDCP*** |                                                          |
+-----------+----------------------------------------------------------+
| **        | Annual report to Congress draws data from a variety of   |
| National\ | sources relating to drug misuse in the U.S. to present   |
| Drug\     | past and current trends, as well as the government's     |
| Control\  | planned strategies and budgets for dealing with the      |
| S         | problems.\                                               |
| trategy** | See http://www.whitehousedrugpolicy.gov/index.html.      |
+-----------+----------------------------------------------------------+
| **DENS**  | 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)u. 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 as     |
|           | abused in addiction treatment programs.                  |
|           |                                                          |
|           | See http://www.densonline.org/ for more information.     |
+-----------+----------------------------------------------------------+
| ***FDA*** | U.S. Food & Drug Administration                          |
|           |                                                          |
| **M       | MedWatch, the FDA Safety Information and Adverse Event   |
| edWatch** | Reporting Program, serves both healthcare professionals  |
|           | and the medical product-using 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 & 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 provision and 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) is designed to collect 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 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 solutions to the         |
|           | pharmaceutical and healthcare industries, offering       |
|           | business intelligence products and services including    |
|           | marketing data on prescription and over-the-counter      |
|           | pharmaceutical products.                                 |
|           |                                                          |
|           | IMS tracks and measure 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.                                |
+-----------+----------------------------------------------------------+
| *         | On June 27, 2002, Purdue Pharma announced establishment  |
| *RADARS** | of the Researched Abuse, Diversion and Addiction-Related |
|           | Surveillance (RADARS™) System, an initiative 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. Data          |
|           | collection was expected to be completed during fall or   |
|           | early winter of 2002. As experience with the System      |
|           | accumulates, other types of medications, such as         |
|           | benzodiazepines (alprazolam and diazepam), would be      |
|           | added. Database is not open to the public.               |
|           |                                                          |
|           | See: http://www.purduepharma.com.                        |
+-----------+----------------------------------------------------------+
| ***OT     | National Violent Death Reporting System (NVDRS) is a     |
| HER...*** | recent State-based initiative funded by the CDC that     |
|           | tracks violent deaths resulting from the use of physical |
| **NVDRS** | force, 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\   | 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.                   |
+-----------+----------------------------------------------------------+
| **CP      | Consumer Product Safety Commission (CPSC) uses death     |
| SC/NISS** | certificate data for a National Injury Surveillance      |
|           | System (NISS). 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        |
|           | initiated by many States to provide data for public      |
|           | health initiatives, law enforcement, and the promotion   |
|           | of early intervention and prevention of drug-related     |
|           | problems. PMPs rely on pharmacies and other drug         |
|           | dispensers to send data electronically to central        |
|           | 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/                  |
+-----------+----------------------------------------------------------+

*Access to all web sites verified in April 2003*

# Appendix B. Past Investigations of Methadone-Associated Mortality 

  -------------------------------------------------------------------------------------------------
  **Epidemiologic /                                                 
  Descriptive Studies of                                            
  Methadone-Associated                                              
  Mortality\                                                        
  ***(listed by latest                                              
  year of data                                                      
  collection; may not                                               
  include all studies)*                                             
  ---------------------- ------------------- ---------------------- -------------------------------
  **Reference**          **Location/Date**   **Subjects/Design**    **Comments**

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

  Gardner 1970           London\             Descriptive study of   Concludes that at least 7
                         1965 -- 69          12 methadone deaths.   deaths occurred due to lack of
                                                                    opioid tolerance, and 8 were
                                                                    due to prescription of too high
                                                                    a starting dose (greater than
                                                                    70 mg).

  Baden 1970             New York\           Report on 24 deaths in Half of methadone deaths
                         1967 -- 70          methadone program; 8   related to abuse of alcohol and
                                             not in OTP.            other drugs. Of 8
                                                                    methadone-associated deaths
                                                                    outside OTP, 5 were oral
                                                                    overdose (2 in opioid naïve
                                                                    victims), 3 were IV abuse of
                                                                    methadone.

  Gearing & Schweitzer   New York\           Long term descriptive  Reasons for the causes of death
  1974                   1964 -- 71          study on outcomes of   in 153 subjects not detailed,
                                             subjects in OAT.       but at least 30 percent were
                                                                    polydrug-related.

  Roizin et al. 1972     New York\           Series of 14 deaths,   Methadone dose range 40-180
                         1972                57 percent receiving   mg/d. Polydrug abuse implicated
                                             methadone.             in most cases, 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 -- 73                                 streets -- 46.2 percent of
                                                                    decedents were not opioid
                                                                    tolerant -- and was curtailed
                                                                    sharply by restricting access
                                                                    to licensed clinics rather than
                                                                    private physicians.

  Appel et al. 2000      New York\           176 deaths among 1,544 Overall, 93 deaths during
                         1966 -- 76          patients in and out of methadone tx; 83 after leaving
                                             OAT program.           treatment, although rate/1,000
                                                                    person years was double
                                                                    posttreatment. Only 2 deaths
                                                                    during OAT were opioid related.

  Concool et al. 1979    East Harlem, NY\    Review of deaths in    Mortality rate was 20 per 1000
                         1969 -- 76          patients enrolled in   patients, deaths largely due to
                                             OAT; risk assessment.  alcoholism and violence. None
                                                                    of the deaths directly
                                                                    attributed to methadone.

  Caplan et al. 1983     Maryland\           77 deaths with         18 deaths with methadone as
                         1975 -- 80          methadone present.     sole agent; overlap in serum
                                                                    methadone levels among
                                                                    sole-agent deaths, polydrug
                                                                    deaths, and non-drug-related
                                                                    deaths with methadone present.

  Kringsholm et al. 1988 Denmark\            Descriptive study of   20 percent of drug deaths
                         1868 -- 86          drug deaths.           during abstinence were due to
                                                                    methadone. No details of
                                                                    circumstances provided.

  Petry et al.\          New York\           Review of 325 deaths   During 12-year period deaths
  1998                   1975 -- 86          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
                         1981 -- 86          deaths associated with methadone, of which 3 were in
                                             methadone.             the first two weeks of
                                                                    starting, 6 less than two weeks
                                                                    after leaving OAT; 9 caused by
                                                                    a combination of opioids and
                                                                    methadone. 15 deaths were
                                                                    associated with benzodiazepine
                                                                    use.

  Davoli et al. 1993     Italy\              Matched case control   Higher risk of overdose death
                         1980 -- 88          analysis of IV drug    for subjects who had left
                                             abusers in OAT.        methadone treatment
                                                                    particularly within first year
                                                                    (Odds Ratio 7.98).

  Drummer et al. 1990,   Victoria,\          10 death in            Deaths were in early stages of
  1992                   Australia 1990      methadone-treated      OAT, dose range 45--70 mg (mean
                                             patients.              53 mg). Six had additional
                                                                    CNS-active drugs present; all
                                                                    had chronic hepatitis; 5 had
                                                                    bronchopneumonia.

  Kringsholm et al. 1994 Denmark\            Descriptive study of   Against a background of
                         1987 -- 91          drug deaths.           increasing fatalities, with
                                                                    most also involving IV heroin,
                                                                    methadone poisoning cases
                                                                    increased significantly in
                                                                    1991. About half of the victims
                                                                    were receiving methadone
                                                                    maintenance at time of death.

  Neeleman and Farrell   England &\          Retrospective          Poisoning deaths involving
  1997                   Wales\              longitudinal survey.   methadone (alone or in
                         1974 -- 92                                 combination) rose 80 percent
                                                                    per 3-year period. However,
                                                                    there was no evidence that this
                                                                    was disproportional to
                                                                    increases in heroin deaths.

  Barrett et al. 1996    Harris County,      Investigation of 91    CDC team of investigators found
                         Texas\              deaths involving       85 percent of cases involved
                         1987 -- 92          methadone.             polydrug abuse and only 20
                                                                    percent of decedents were in
                                                                    OAT at time of death. Only 11
                                                                    cases attributed directly to
                                                                    methadone toxicity.

  La Harpe & Fryc 1995   Geneva\             Description of 24      No deaths occurred in first two
                         1987 -- 93          deaths associated with weeks of methadone tx, 3 in
                                             methadone.             less than 2 weeks after leaving
                                                                    OAT, 11 occurred with
                                                                    concomitant benzodiazepines, 8
                                                                    with alcohol, and 11 in
                                                                    presence of heroin.

  Goldstein & Herrera    Albuquerque\        Long term follow--up   34 percent had died over 22
  1995                   1971 -- 93          of 1,019 patients      years since first starting
                                             registered in          methadone; more than one-third
                                             methadone OAT.         related to drug abuse. Causes
                                                                    of death not provided. Subjects
                                                                    were 4-6 times more likely to
                                                                    die than non--addicts.

  Clark et al. 1995      Sheffield, UK\      18 subjects, case      Reported death of 7 subjects in
                         1991 -- 94          study.                 early stages of methadone tx,
                                                                    dose range 30-100 mg; 3 died
                                                                    after long term use, eight died
                                                                    from non-prescribed drug use.
                                                                    Multiple drug use was common
                                                                    but not considered to have
                                                                    played a major role in most
                                                                    deaths.

  Cairns et al. 1996     Manchester\         90 subjects, case      Showed increase in number of
                         1985 -- 1994        study.                 methadone deaths during this
                                                                    period; methadone was sole
                                                                    cause of death in 52 and 36
                                                                    died from non--prescribed use.
                                                                    Methadone cases represented 15
                                                                    percent of total fatal
                                                                    drug-overdoses during period.

  Williamson et al. 1997 South Australia\    47 fatalities with     Widespread use of methadone
                         1984 -- 94          risk assessment .      tablets for chronic pain led to
                                                                    disproportionate increase in
                                                                    deaths (7 fold over use of
                                                                    syrup), sudden increase in
                                                                    deaths in 1993-94 with build up
                                                                    of private methadone clinics.

  Caplehorn 1998         Sydney 1994         13 subjects, case      10 died in first two weeks
                                             study.                 during methadone induction,
                                                                    last dose range 25--110 mg,
                                                                    median 40 mg.

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

  Zador & Sunjic 2000    NSW Australia\      238                    44 percent of deaths were drug
                         1990 -- 95          methadone-associated   related with most (92 percent)
                                             deaths examined.       involving polydrug abuse, and
                                                                    42 percent occurred during the
                                                                    first week of methadone
                                                                    treatment.

  Drummer 1997           Victoria,           89 deaths with         Toxic methadone concentrations
                         Australia\          methadone detected.    overlapped those in
                         1994 -- 97                                 non-drug-related deaths with
                                                                    methadone present. Those
                                                                    starting OAT or who used the
                                                                    drug occasionally were most at
                                                                    risk of death.

  Valmana et al. 2000    London 1997         Review of 40           Methadone had not been
                                             methadone-associated   prescribed in 72 percent of
                                             deaths                 cases and these decedents were
                                                                    younger (median 22 yrs) than
                                                                    the prescribed-methadone
                                                                    victims (median 37 years),
                                                                    suggesting more chaotic abuse
                                                                    patterns in younger persons.

  Perret et al. 2000     Geneva,             36 methadone cases,    Nearly all (35) had illicit
                         Switzerland\        out of 106 total drug  drugs combined with methadone,
                         1994 -- 98          abuse fatalities.      21 were attributed as due to
                                                                    methadone lethality and only a
                                                                    third of those decedents were
                                                                    in OAT. Methadone-attributed
                                                                    deaths remained constant at
                                                                    3-5/yr throughout study period,
                                                                    while overall drug abuse deaths
                                                                    declined markedly.

  Eastwood 1998          London 1998         Description of 13      13 children poisoned with
                                             childhood deaths.      methadone syrup prescribed to
                                                                    one or more of the
                                                                    opioid--dependent parents; five
                                                                    died. Methadone serum
                                                                    concentrations of deceased
                                                                    children overlapped those
                                                                    children who survived.

  Karch & Stephens 2000  San Francisco\      38 cases (out of 3,317 Methadone was cited as cause of
                         1997 -- 98          examined) involving    death in 21 cases, although
                                             methadone.             blood methadone concentration
                                                                    was identical in this group and
                                                                    the group in whom methadone was
                                                                    an incidental finding.

  Buster et al. 2002     Amsterdam\          5,200                  68 overdose deaths recorded,
                         1986 -- 98          methadone-maintained   with a modest increase during
                                             patients observed.     first 2 weeks of treatment.
                                                                    Overall death rate was 2.3/1000
                                                                    patient-years.

  Heinemann et al. 2000  Hamburg, Germany\   Surveillance on        Rising cases of
                         1990 -- 99          drug-related           methadone-related fatalities
                                             poisonings.            coincided with declines in
                                                                    heroin deaths. 65 percent of
                                                                    methadone decedents were not in
                                                                    an OTP.

  Bartu et al. 2002      Western Australia\  84 methadone-related   74 percent of deaths caused by
                         1993 -- 99          deaths evaluated.      combination of drug effects,
                                                                    with benzodiazepines present in
                                                                    3/4 of those cases. 57 percent
                                                                    were not in an OTP at time of
                                                                    death. Methadone-associated
                                                                    mortality peaked in 1998 at
                                                                    7.7/1000 patients treated, one
                                                                    year after expansion into the
                                                                    private sector.

  Green et al. 2000      South Australia\    35 cases of methadone  10 victims were receiving
                         1996 -- 99          causing or             methadone maintenance tx, of
                                             contributing to death. whom 4 died within first week.
                                                                    Eight non-OAT cases involved
                                                                    diverted methadone, with 7
                                                                    including other drugs. Mean age
                                                                    of decedents was 25 years.

  Oliver et al. 2002     Sheffield, UK\      82 drug-abuse related  Deaths attributed wholly or
                         1997 -- 99          deaths                 partially to methadone declined
                                                                    from 37 percent to 18 percent
                                                                    during the 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 despite 18
                                             deaths.                percent increases in methadone
                                                                    prescriptions since that year.
                                                                    45 percent of deaths involved
                                                                    persons not prescribed
                                                                    methadone, all but 2 involved
                                                                    drug abuse-related causes, none
                                                                    in persons within one month of
                                                                    starting methadone maintenance.
                                                                    Of those on methadone
                                                                    prescription, 60 percent were
                                                                    on observed dosing at time of
                                                                    death.
  -------------------------------------------------------------------------------------------------

# Appendix C. 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 D. MedWatch Form

![](media/image17.png){width="6.330555555555556in"
height="8.105555555555556in"}

# Appendix E. 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/image18.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 F. 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.