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Opioids in the Management of Chronic Non-Cancer Pain: An Update of American Society of the Interventional Pain Physicians' (ASIPP) Guidelines

Authors:
  • The Helm Center for Pain Management
  • Millennium Pain Center

Abstract and Figures

Opioid abuse has continued to increase at an alarming rate since our last opioid guidelines were published in 2005. Available evidence suggests a continued wide variance in the use of opioids, as documented by different medical specialties, medical boards, advocacy groups, and the Drug Enforcement Administration. The objectives of opioid guidelines by the American Society of Interventional Pain Physicians (ASIPP) are to provide guidance for the use of opioids for the treatment of chronic non-cancer pain, to bring consistency in opioid philosophy among the many diverse groups involved, to improve the treatment of chronic non-cancer pain, and to reduce the incidence of abuse and drug diversion. A broadly based policy committee of recognized experts in the field evaluated the available literature regarding opioid use in managing chronic non-cancer pain. This resulted in the formulation of the review and update of the guidelines published in 2006, a series of potential evidence linkages representing conclusions, followed by statements regarding the relationships between clinical interventions and outcomes. The elements of the guideline preparation process included literature searches, literature synthesis, consensus evaluation, open forum presentations, formal endorsement by the Board of Directors of the American Society of Interventional Pain Physicians, and peer review. Based on the criteria of the U.S. Preventive Services Task Force, the quality of evidence was designated as Level I, II, and III, with 3 subcategories in Level II, with Level I described as strong and Level III as indeterminate. The recommendations were provided from 1A to 2C, varying from strong recommendation with high quality evidence to weak recommendation with low-quality or very low-quality evidence. After an extensive review and analysis of the literature, which included systematic reviews and all of the available literature, the evidence for the effectiveness of long-term opioids in reducing pain and improving functional status for 6 months or longer is variable. The evidence for transdermal fentanyl and sustained-release morphine is Level II-2, whereas for oxycodone the level of evidence is II-3, and the evidence for hydrocodone and methadone is Level III. There is also significant evidence of misuse and abuse of opioids. The recommendation is 2A - weak recommendation, high-quality evidence: with benefits closely balanced with risks and burdens; with evidence derived from RCTs without important limitations or overwhelming evidence from observational studies, with the implication that with a weak recommendation, best action may differ depending on circumstances or patients' or societal values. Opioids are commonly prescribed for chronic non-cancer pain and may be effective for short-term pain relief. However, long-term effectiveness of 6 months or longer is variable with evidence ranging from moderate for transdermal fentanyl and sustained-release morphine with a Level II-2, to limited for oxycodone with a Level II-3, and indeterminate for hydrocodone and methadone with a Level III. These guidelines included the evaluation of the evidence for the use of opioids in the management of chronic non-cancer pain and the recommendations for that management. These guidelines are based on the best available evidence and do not constitute inflexible treatment recommendations. Because of the changing body of evidence, this document is not intended to be a "standard of care."
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Opioids in the Management of Chronic
Non-Cancer Pain: An Update of American
Society of the Interventional Pain Physicians’
(ASIPP) Guidelines
Andrea M. Trescot, MD, Standiford Helm, MD, Hans Hansen, MD, Ramsin Benyamin, MD,
Scott E. Glaser, MD, Rajive Adlaka, MD, Samir Patel, DO, and Laxmaiah Manchikanti, MD
www.painphysicianjournal.com
Pain Physician 2008: Opioids Special Issue: 11:S5-S62 • ISSN 1533-3159
Background: Opioid abuse has continued to increase at an alarming rate since our last opi-
oid guidelines were published in 2005. Available evidence suggests a continued wide vari-
ance in the use of opioids, as documented by different medical specialties, medical boards,
advocacy groups, and the Drug Enforcement Administration.
Objectives: The objectives of opioid guidelines by the American Society of Interventional
Pain Physicians (ASIPP) are to provide guidance for the use of opioids for the treatment of
chronic non-cancer pain, to bring consistency in opioid philosophy among the many diverse
groups involved, to improve the treatment of chronic non-cancer pain, and to reduce the in-
cidence of abuse and drug diversion.
Design: A broadly based policy committee of recognized experts in the field evaluated the
available literature regarding opioid use in managing chronic non-cancer pain. This resulted
in the formulation of the review and update of the guidelines published in 2006, a series of
potential evidence linkages representing conclusions, followed by statements regarding the
relationships between clinical interventions and outcomes.
Methods: The elements of the guideline preparation process included literature searches,
literature synthesis, consensus evaluation, open forum presentations, formal endorsement by
the Board of Directors of the American Society of Interventional Pain Physicians, and peer re-
view. Based on the criteria of the U.S. Preventive Services Task Force, the quality of evidence
was designated as Level I, II, and III, with 3 subcategories in Level II, with Level I described as
strong and Level III as indeterminate. The recommendations were provided from 1A to 2C,
varying from strong recommendation with high quality evidence to weak recommendation
with low-quality or very low-quality evidence.
Results: After an extensive review and analysis of the literature, which included systematic
reviews and all of the available literature, the evidence for the effectiveness of long-term opi-
oids in reducing pain and improving functional status for 6 months or longer is variable. The
evidence for transdermal fentanyl and sustained-release morphine is Level II-2, whereas for
oxycodone the level of evidence is II-3, and the evidence for hydrocodone and methadone is
Level III. There is also significant evidence of misuse and abuse of opioids.
The recommendation is 2A weak recommendation, high-quality evidence: with benefits
closely balanced with risks and burdens; with evidence derived from RCTs without impor-
tant limitations or overwhelming evidence from observational studies, with the implication
that with a weak recommendation, best action may differ depending on circumstances or
patients’ or societal values.
Conclusion: Opioids are commonly prescribed for chronic non-cancer pain and may be ef-
fective for short-term pain relief. However, long-term effectiveness of 6 months or longer is
variable with evidence ranging from moderate for transdermal fentanyl and sustained-re-
From: American Society of
Interventional Pain Physicians.
Sukdeb Datta, MD, Nalini Sehgal,
MD, James Colson, MD, Art
Jordan, MD, and Marion Lee, MD,
contributed in preparation of these
guidelines.
Additional author information is
available on S51.
Address correspondence:
ASIPP
81 Lakeview Drive
Paducah, Kentucky 42003
E-mail: asipp@asipp.org
Disclaimer: There was no external
funding in the preparation of this
manuscript.
Conflict of interest: Internal funding
provided by the American Society
of Interventional Pain Physicians
was limited to travel and lodging
expenses of the authors.
Free full manuscript:
www.painphysicianjournal.com
Pain Physician 2008: Opioids Special Issue: 11:S5-S62
S6 www.painphysicianjournal.com
1.0 INTRODUCTION
1.1 Purpose
1.2 Rationale and Importance
1.3 Objectives and Benefits
1.4 Population and Preferences
1.5 Implementation and Review
1.6 Application
1.7 Focus
1.8 Methodology
2.0 CHRONIC PAIN
2.1 Definitions
2.2 Prevalence
2.3 Chronicity
2.4 Health and Economic Impact
2.5 Comorbidities
3.0 OPIOIDS USE IN CHRONIC PAIN
3.1 General Considerations
3.2 Response to Alleged Undertreatment
3.3 Prescription Opioids in Chronic Pain
3.4 Nonmedical Use of Prescription Drugs
3.4.1 Physician Survey Highlights
3.4.2 Pharmacist Survey Highlights
3.4.3 Drug Abuse Warning Net
-
work (DAWN) Reports
3.4.4 Healthcare and Social Costs
3.5 Substance Abuse in Chronic Pain
3.6 Economic Impact
3.7 Drug Diversion
3.8 Controlling Diversion and Abuse
3.8.1 Drug Enforcement Administration (DEA)
3.8.2 State Laws and Regulations
3.8.3 Prescription Drug Monitor
-
ing Programs (PDMP)
4.0 PHARMACOLOGICAL CONSIDERATIONS
4.1 Opioid Pharmacology
4.1.1 Opioid Receptors
4.1.2 Opioid Categories
4.1.3 Opioid Metabolism
4.2 Adverse Effects
4.3 Drug Interactions
4.4 Drug Conversions
4.5 Opioid Therapy and Side Effects
5.0 TERMINOLOGY OF ABUSE AND ADDICTION
5.1 Introduction
5.2 History
5.3 Terminology
5.3.1 Substance Abuse
5.3.2 Substance Dependence
5.3.3 Tolerance
5.3.4 Withdrawal
5.3.5 Physical Dependence
5.3.6 Addiction
5.4 Opioid Agonist Therapy
6.0 CLINICAL EFFECTIVENESS
6.1 Introduction
6.2 Systematic Reviews
6.2.1 Effectiveness of Individual Drugs
6.3 Summary of Evidence
6.4 Recommendation
7.0 ADHERENCE MONITORING
7.1 Introduction
7.2 Screening for Opioid Abuse
7.3 Urine Drug Testing (UDT)
7.4 Periodic Review and Monitoring
7.4.1 Periodic Review
7.4.2 Periodic Monitoring
7.4.3 Prescription Drug Monitoring
7.4.4 Periodic Education
7.4.5 Pill Counts
8.0 PRINCIPLES OF OPIOID USAGE
8.1 Introduction
8.2 Recommendation
8.3 Basic Philosophy
8.4 Evaluation
8.4.1 Diagnostic and Therapeutic Injections
8.4.2 Consultation
8.4.3 Informed Consent and Con
-
trolled Substance Agreement
9.0 DOCUMENTATION AND MEDICAL RECORDS
10.0 KEY POINTS
lease morphine with a Level II-2, to limited for oxycodone with a Level II-3, and indeterminate for hydrocodone and metha-
done with a Level III.
These guidelines included the evaluation of the evidence for the use of opioids in the management of chronic non-cancer
pain and the recommendations for that management. These guidelines are based on the best available evidence and do not
constitute inflexible treatment recommendations. Because of the changing body of evidence, this document is not intend-
ed to be a “standard of care.”
Key words: Chronic pain, persistent pain, non-cancer pain, controlled substances, substance abuse, prescription drug
abuse, dependency, opioids, prescription monitoring, drug testing, adherence monitoring, diversion
Pain Physician 2008; 11:S5-S62
www.painphysicianjournal.com S7
ASIPP Opioid Guidelines
1.0 IntroductIon
1.1 Purpose
The American Society of Interventional Pain Phy-
sicians (ASIPP) has developed guidelines for the use of
opioids in the management of non-cancer pain. They
were last updated and published in Pain Physician
journal in 2006 (1). These guidelines have been de-
veloped by ASIPP, so that physicians, lawmakers, and
law enforcement agencies would better understand
the role of opioids in non-cancer pain management
algorithms. A better understanding of the risks and
benefits of this class of medications should conceiv-
ably improve access to treatment for patients with
chronic pain whose quality of life could be improved
with opioids. In addition, a better understanding of
the risks and benefits should also conceivably lead to
a reduction in the abuse and diversion of this class
of medications, consequences which are of grave im-
portance. Many opioid proponent experts and some
policy makers maintain that chronic pain remains un-
dertreated with opioids and that the extent of the
problem may have been underestimated. Similarly,
some experts and many policy makers maintain that
chronic pain may have been overtreated with opioids
and the extent of the problem of abuse, diversion,
and deaths may have been underestimated (2-8). Re-
gardless of these widely diverse opinions, there is in-
controvertible evidence that we are in the midst of
an epidemic of prescription drug abuse and this has
become a public health issue as well (2-5).
1.2 Rationale and Importance
The use of opioids in the management of can-
cer pain and palliative care has been widely accepted.
The use of opioids to treat moderate to severe acute
pain is also widely accepted. The use of opioids to
treat chronic non-cancer pain, however, remains con-
troversial (6,7,9-18). The most significant consequenc-
es of long-term therapy include, but are not limited
to, tolerance, physical and psychological dependence,
abuse, and diversion (6,7-18). When utilized to treat
cancer pain or in palliative care, the treatment ob-
jectives of pain control can typically be met, and the
major concerns regarding the prolonged use of opi-
oids do not have as much impact on therapeutic deci-
sion-making. This is also usually true when treating
acute pain. These issues, however, are of grave conse-
quence when considering the prescription of opioids
for chronic benign pain with evidence of lack of ef-
fectiveness and significant complications (6-19).
Another significant factor that accounts for the
discrepancy in the acceptance of the use of opioids for
chronic benign pain is the actual goals of treatment
in this patient population. The treatment objectives
in chronic benign pain are subtly, but significantly,
different and more complex than the goals of opioid
therapy in the settings of terminal conditions or acute
pain. The objective of the treatment of chronic pain of
a non-cancer origin include, when possible, not only
management of painful symptoms but an emphasis on
maintaining functionality and continued participation
in society. These objectives can be thwarted by the use
of opioids depending on multiple factors. These factors
include, but are not limited to, the psychological make
up of the patient, the type of pain being treated, and
the skills, knowledge, and resources of the clinician.
1.3 Objectives and Benefits
The objective of these guidelines is to provide
clear and concise guidelines to physicians, to improve
patient access, and avoid diversion and abuse. The
perceived benefits of these guidelines include:
Increased physician awareness about the current
issues involving opioids and non-cancer pain
Improved patient access
Reduced level of opioid abuse
Improved ability to manage patient expectations
Reduced diversion
Improved understanding by law enforcement
about proper prescribing patterns
Improved cooperation among patients, providers,
and regulatory agencies
Improved understanding by patients regarding
their rights as well as their responsibilities when
taking opioid medications
1.4 Population and Preferences
The population covered by these guidelines in-
cludes all patients with chronic moderate to severe
pain of non-cancer origin who may be eligible for ap-
propriate medically necessary opioid analgesic man-
agement. This management may include or be inde-
pendent of interventional techniques.
1.5 Implementation and Review
The dates for implementation and review were
established:
Effective date – February 1, 2008
Scheduled review – July 1, 2011
Expiration date – January 31, 2012
Pain Physician 2008: Opioids Special Issue: 11:S5-S62
S8 www.painphysicianjournal.com
1.6 Application
These guidelines were developed to be used by
physicians practicing interventional pain manage-
ment and do not constitute inflexible treatment rec-
ommendations. These guidelines are not intended to
address all possible clinical situations where opioids
might be used for non-cancer pain in clinical practice.
It is expected that a provider will establish a plan
of care on a case-by-case basis, taking into account
an individual patient’s medical condition, personal
needs, and preferences, as well as the physicians
experience. Based on an individual patient’s needs,
treatment different from that outlined here could be
warranted. These guidelines do not represent stan-
dard of care.”
1.7 Focus
The focus of these guidelines is the effective man-
agement of chronic non-cancer pain, as well as the
various issues involved in opioid administration. It is
recognized that management of chronic non-cancer
pain takes place in a wide context of healthcare, in-
volving multiple specialists and multiple techniques.
Guidelines cannot be applied to all patients. Conse-
quently, the decision to implement a particular man-
agement approach should be based on a comprehen-
sive assessment of the patient’s overall health status,
disease state, patient preference, and physician train-
ing and skill.
1.8 Methodology
A policy committee was convened and included
a broad representation of academic and clinical prac-
titioners, representing a variety of practices and geo-
graphic areas, all recognized as experts in opioid use
and management of patients with chronic non-cancer
pain. This committee formalized the essentials of the
guidelines. The elements of the guidelines preparation
process included literature searches, literature synthe-
sis, consensus evaluations, open forum presentations,
formal endorsement by the ASIPP board of directors
and peer review (20-40).
Evidence-based medicine is defined as the con-
scientious, explicit, and judicious use of current best
evidence in making decisions about the care of indi-
vidual patients (41). It is not “cookbook” medicine,
but instead requires an integration of the best exter-
nal evidence combined with individual clinical exper-
tise and the patient’s choice. While an evidence-based
approach may seem to enhance the scientific rigor of
guideline development, recommendations may not
always meet the highest scientific standards (42). The
study of pain treatments has been limited due to the
subjective nature of pain, especially non-cancer pain,
and the effectiveness of interventions (such as the use
of opioids) has to be judged relative to non-interven-
tion (39,43-50).
In preparation of these guidelines, it is recognized
that at the core of an evidence-based approach to clin-
ical or public health issues is, inevitably, the evidence
itself, which needs to be carefully gathered and collat-
ed from a systematic literature review of the particu-
lar issues. It follow that process by which the strength
of scientific evidence is evaluated in the development
of evidence-based medicine recommendations and
guidelines is crucial. The practice of evidence-based
medicine requires the integration of individual clini-
cal expertise with the best available clinical evidence
from systematic research.
Systems for grading the strength of a body of
evidence are much less uniform and consistent than
those for rating study quality (24-40). Consequently,
the guideline committee designed levels of evidence
from Level I through Level III, adapted from the U.S.
Preventive Services Task Force (USPSTF) (26) as shown
in Table 1.
Table 1. Quality of evidence.
I: Evidence obtained from at least one properly randomized controlled trial.
II-1: Evidence obtained from well-designed controlled trials without randomization.
II-2: Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one center or research group.
II-3: Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled experiments (such as
the results of the introduction of penicillin treatment in the 1940s) could also be regarded as this type of evidence.
III: Opinions of respected authorities, based on clinical experience descriptive studies and case reports or reports of expert committees.
Adapted from the Agency for Healthcare Research and Quality U.S. Preventive Services Task Force (USPSTF) (Ref. 24)
www.painphysicianjournal.com S9
ASIPP Opioid Guidelines
Pain that persists beyond the usual course of an
acute disease or a reasonable time for any injury
to heal that is associated with chronic pathologic
processes that cause continuous pain or pain at
intervals for months or years
Persistent pain that is not amenable to routine
pain control methods.
2.2 Prevalence
Any description of the epidemiology of chronic
pain starts with its significance as a national public
health problem. In a survey of chronic pain in America
conducted by the American Pain Society (an advo-
cacy group), 9% of the adult population was shown
Recommendations were provided based on meth-
odological quality of supporting evidence, benefit ver-
sus risks and burdens, and implications (37) (Table 2).
2.0 chronIc PaIn
2.1 Definitions
Acute pain is a vital, protective mechanism that
allows us to live in an environment filled with poten-
tial dangers. On the other hand, chronic pain serves
no such physiologic function, and is itself not a use-
ful symptom. Chronic pain is difficult to define. Con-
sequently, a combination of multiple definitions must
be utilized.
Table 2. Grading recommendations.
Grade of Recommendation/
Description
Benefit vs Risk and
Burdens
Methodological Quality of
Supporting Evidence Implications
1A/strong recommendation,
high-quality evidence
Benefits clearly outweigh
risk and burdens, or vice
versa
RCTs without important limitations
or overwhelming evidence from
observational studies
Strong recommendation,
can apply to most patients in
most circumstances without
reservation
1B/strong recommendation,
moderate quality evidence
Benefits clearly outweigh
risk and burdens, or vice
versa
RCTs with important limitations
(inconsistent results, methodological
flaws, indirect, or imprecise) or
exceptionally strong evidence from
observational studies
Strong recommendation,
can apply to most patients in
most circumstances without
reservation
1C/strong recommendation,
low-quality or very low-quality
evidence
Benefits clearly outweigh
risk and burdens, or vice
versa
Observational studies or case series Strong recommendation but
may change when higher quality
evidence becomes available
2A/weak recommendation, high-
quality evidence
Benefits closely balanced
with risks and burden
RCTs without important limitations
or overwhelming evidence from
observational studies
Weak recommendation, best
action may differ depending on
circumstances or patients’ or
societal values
2B/weak recommendation,
moderate-quality evidence
Benefits closely balanced
with risks and burden
RCTs with important limitations
(inconsistent results, methodological
flaws, indirect, or imprecise) or
exceptionally strong evidence from
observational studies
Weak recommendation, best
action may differ depending on
circumstances or patients’ or
societal values
2C/weak recommendation,
low-quality or very low-quality
evidence
Uncertainty in the estimates
of benefits, risks, and
burden; benefits, risk, and
burden may be closely
balanced
Observational studies or case series Very weak recommendations;
other alternatives may be equally
reasonable
Adapted from Guyatt et al (37). Grading strength of recommendations and quality of evidence in clinical guidelines. Report from an American
College of Chest Physicians task force. Chest 2006; 129:174-181.
Pain Physician 2008: Opioids Special Issue: 11:S5-S62
S10 www.painphysicianjournal.com
to suffer from moderate to severe, non-cancer-re-
lated pain (51). Further, two-thirds of these people
have been living with the pain for over 5 years and
the pain was found to have a significant impact on
the quality of life and emotional well-being, with pa-
tients experiencing significant improvements in these
factors when their pain was well controlled. Other
studies have shown the prevalence of chronic pain in
the adult population ranging from 2% to 40%, with
a median point prevalence of 15% (52,53). Persistent
pain was reported with an overall prevalence of 20%
of primary care patients, with approximately 48% re-
porting back pain (54). A systematic review of 4 in-
ternational studies conducted in developed countries
found prevalence rates of any type and severity level
of chronic pain ranging from 10.5% to 55.2% of the
population (55). A European survey of 46,000 indi-
viduals showed that 1 in 5 people reported suffering
from chronic pain (56). This survey also showed that
chronic pain sufferers reported 7 years of chronic pain
on average, with some reporting pain lasting more
than 20 years. A survey of Americans (57) showed 9%
of Americans suffer with moderate-to-severe chronic
non-cancer pain. An Australian study of over 17,000
people (53) showed the prevalence of chronic pain in
17.1% of males and 20% of females with the preva-
lence for males peaking at 27% in the 65–69 year age
group and for females, prevalence peeking at 31% in
the oldest age group of 80–84 years. Further, chronic
pain is not only seen in adults, but it is also seen in the
elderly and children (58-63). Various non-cancer pain
problems include spinal pain, osteoarthritis, ischemic
pain syndromes, visceral pain syndromes, neuropathic
pain syndromes, and headache.
Recent publications have confirmed the above
reported findings. Estimates of the prevalence of ar-
thritis and other rheumatic conditions in the United
States (64,65), showed more than 21% of U.S. adults,
or 46.4 million persons, were found to have self-
reported, physician-diagnosed arthritis. This study
estimated that rheumatoid arthritis affects 1.3 mil-
lion adults (down from the estimate of 2.1 million
for 1995), juvenile arthritis affects 294,000 children,
spondylarthritides affects from 0.6 million to 2.4
million adults, systemic lupus erythematosus affects
161,000 to 332,000 adults, systemic sclerosis affects
49,000 adults, and primary Sjögren’s syndrome af-
fects from 0.4 million to 3.1 million adults (64). Part
II of this study (65) also estimated that among U.S.
adults, nearly 27 million have clinical arthritis (up
from the estimate of 21 million for 1995), 711,000
have polymyalgia rheumatica, 228,000 have giant
cell arteritis, up to 3.0 million have had self-reported
gout in the past year (up from the estimate of 2.1
million for 1995), 5.0 million have fibromyalgia, 4 to
10 million have carpal tunnel syndrome, 49 million
have had low back pain in the past 3 months, and
30.1 million have had neck pain in the past 3 months.
These reports are considered to be the best available
prevalence estimates for the United States, but for
most specific conditions, more studies generalizable
to the United States for addressing understudied
populations are needed.
Neuropathic pain is apparently common, with an
estimated prevalence in the general population of 7
to 8% (66-68). However, because neuropathic pain
consists of a number of different disease-specific in-
dications, each of which can have differing diagnostic
definitions and cutoffs, it is difficult to estimate pre-
cisely its prevalence and incidence (69). Neuropathic
pain also affects between 8% and 50% of all diabet-
ics (70). Diabetic peripheral neuropathy shares certain
similarities (both in clinical presentation and response
to treatment) with other forms of neuropathic pain.
The prevalence of neuropathic pain after thoracic sur-
gery is high, with 57% complaining of neuropathic
pain at 7–12 months, 36% at 4–5 years, and 21% at
6–7 years (71). Breast cancer patients may complain
of “phantom” breast pain for months to years after
surgery (72).
2.3 Chronicity
Duration of pain and its chronicity have been top-
ics of controversy. Conventional beliefs are that most
episodes of low back pain will be short-lived, with 80%
to 90% of attacks resolving in about 6 weeks irrespec-
tive of the administration or type of treatment, and
only 5% to 10% of patients developing persistent back
pain (73-82). However, this commonly held belief has
been questioned, as in reality, the condition tends to
relapse, so that most patients will experience recurrent
episodes. Almost 60% of spinal pain patients have suf-
fered from chronic pain from 2 to 15 years (53,56,73-
82). Further, overwhelming evidence shows that chronic
persistent low back pain and neck pain in children and
adults are seen in up to 60% of the patients, 5 years or
longer after the initial episode (73,76-83).
2.4 Health and Economic Impact
Chronic non-cancer pain is associated with sig-
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ASIPP Opioid Guidelines
nificant economic, societal, and health impact (84-93).
The cost of uncontrolled chronic pain is enormous,
both to individuals and to society as it leads to a de-
cline in the quality of life and disability. Estimates and
patterns of direct healthcare expenditures among in-
dividuals with back pain in the United States reached
$90.7 billion for the year 1998 (84). On average, indi-
viduals with back pain generate healthcare expendi-
tures about 60% higher than do individuals without
back pain ($3,498 per year versus $2,178). It has been
estimated that the cost of healthcare for patients with
chronic pain might exceed the combined cost of treat-
ing patients with coronary artery disease, cancer, and
AIDS (94). In the United States, it was estimated that
the cost of treatment in the first year after failed back
surgery for pain was approximately $18,883 in 1997
(95). Even further, annual healthcare cost incurred by
chronic pain patients, excluding cost for surgical pro-
cedures, may range from $500 to as high as $35,400,
with averages ranging from $12,900 to $18,883 annu-
ally (96,97).
The economic costs for chronic pain in general
have been estimated to be over $86 billion per year
(97). A cross-sectional study, based on survey data
from 28,902 working adults in the USA was reported
in 2003 with 13% of the workforce experiencing a loss
of productivity during a 2 week period due to a com-
mon pain condition (98). In monetary terms, this loss
of productivity was calculated to cost $61.3 billion,
with $14.4 billion due to absenteeism and the rest due
to the survey participants being at work, but with im-
paired productivity due to the pain.
In a recent survey of expenditures and health sta-
tus among adults with back and neck problems (92),
self-reported back and neck problems accounted for
a large proportion of health care expenditures and
spine-related expenditures have increased substan-
tially from 1997 to 2005, without evidence of corre-
sponding improvement in self-assessed health status.
In this national estimate based on annual samples of
survey respondents with and without self-reported
spine problems from 1997 through 2005, a total of
23,045 respondents were sampled in 1997, includ-
ing 3,139 who reported spine problems. In 2005,
the sample included 22,258 respondents, includ-
ing 3,187 who reported spine problems. This survey
showed that in 1997, the adjusted medical cost for
respondents with spine problems was $4,695 (95%
CI, $4,181 to $5,209), compared with $2,731 (95% CI,
$2,557 to $2,904) among those without spine prob-
lems in terms in inflation-adjusted dollars. Converse-
ly, in 2005, the adjusted medical expenditures among
respondents with spine problems was $6,096 (95%
CI, $5670 to $6,522), compared with $3,516 (95% CI,
$3,266 to $3,765) among those without spine prob-
lems. Consequently, total estimated expenditures
among respondents with spine problems increased
65% after adjusting for inflation from 1997 to 2005,
more rapidly than overall health expenditures. This
is in contrast to the estimated proportion of persons
with back or neck problems with self-reported physi-
cal function and limitations increasing from 20.7%
(95% CI, 19.9% to 21.4%) to 24.7% (95% CI, 23.7%
to 25.6%) from 1997 to 2005, which is an increase of
4%.
In one study evaluating the burden and determi-
nants of neck pain in the general population (91) and
in workers (93) after evaluating numerous studies (101
for general population and 109 for workers), the 12-
month prevalence of pain typically ranged between
30 and 50%, while, the 12-month prevalence of ac-
tivity-limiting pain was 1.7% to 11.5% in the general
population, in workers, the annual prevalence of neck
pain varied from 27.1% to 47.8%, with between 11%
and 14.1% of workers limiting their activities due to
neck pain.
2.5 Comorbidities
Chronic pain sufferers are considered to be heavy
users of healthcare services, often presenting with
multiple or unexplained symptoms. Studies indicate
that only 2% to 5% of chronic pain sufferers have
been evaluated or treated by a pain specialist (56,99),
whereas many patients seek alternative practitioners
(100), and a high proportion take prescription or over-
the-counter medications.
Chronic pain also has high functional impairment
impact on the sufferer’s day-to-day function, with
a range of activities being curtailed. Patients with
chronic pain report difficulties with daily chores, social
life, and work, and a higher rate of unemployment
(101-104). It has been shown that 19% of patients had
lost their job because of chronic pain (56). In addition,
chronic pain sufferers have been shown to have low
scores for quality of life (105,106).
Increased comorbidity, disability, and costs have
been described widely in the chronic pain population
(107-126). In a study of 1,484 community dwelling
Australian women 70 to 85 years of age, daily back
pain was shown to be associated with reduced quality
Pain Physician 2008: Opioids Special Issue: 11:S5-S62
S12 www.painphysicianjournal.com
of life, mobility and longevity, and increased risk of
coronary heart events (107). In a descriptive report of
the longitudinal course of depressive symptoms and
pain experienced by continuing care retirement com-
munity residents, in 169 residents, 37% met the cri-
teria for chronic activity-limiting pain, 21% met the
criteria for chronic high depressive symptoms, and
13% were comorbid (63). In another study of an el-
derly population, both pain and depression affected
physical performance, with depression having more
an influential effect on the decline of physical per-
formance and causing increased levels of functional
impairment. This was also confirmed in a prospective
study of patients with disabling low back pain and de-
pressive symptoms in a community-dwelling popula-
tion of over 90,000 elderly, more than 50,000 of whom
were being surveyed for the follow-up purposes after
2 years (109). This study showed that among commu-
nity-dwelling elderly persons, depressive symptoms
and disabling low back pain were widespread, with
depressive symptoms predicting disabling low back
pain and vice versa. Multiple studies have addressed
the impact of chronic spinal pain (112-114), headache
(115,117,118), and various types of pain.
Extensive research of involvement of psycho-
logical disorders in the chronic pain population has
been published (120-134). Since pain is defined as
both a physiological sensation and a psychological
condition or state (126), the neural event of pain
is in many ways inextricable from the psychologi-
cal or phenomenological experience of pain (127).
Consequently, chronic pain in particular manifests a
psychological constellation of cognitive, emotional,
and behavioral characteristics. Numerous studies
have shown that a significant proportion of pain pa-
tients present with depression, anxiety, and somati-
zation disorder, either alone or in combination (120-
125,128-133). In studies that have evaluated chronic
pain patients, the comorbidity of major depression
ranged from 15% to 56%, significantly higher than
the occurrence of major depression within the gen-
eral population, which ranged from 5% to 10%.
Similarly, the occurrence of somatization disorder
ranged from 20% to 31% in chronic pain patients,
compared to 1% to 4% in the general population.
Consequently, the prevalence of pain is noted to
increase with the association of comorbidities, and
the prevalence of pain continues to increase, along
with psychological and substance abuse disorders.
3.0 oPIoIds use In chronIc PaIn
3.1 General Considerations
Inadequate treatment of pain has been attributed
to a lack of knowledge about pain management op-
tions, inadequate understanding of addiction, or fears
of investigation or sanction by federal, state, and local
regulatory agencies (1-6,134-136). Proponents of opi-
oid drug therapy for all types of pain contend that opi-
oid analgesic therapy plays an important role in pain
management and should be available when needed
for the treatment of all kinds of pain, including non-
cancer pain, without restriction of dosage or frequency
(135). Further, the Drug Enforcement Adminstration
(DEA) has also taken the position that clinicians should
be knowledgeable about using opioids to treat pain,
and should not hesitate to prescribe them when opi-
oids are the best clinical choice of treatment (137). In
addition to the DEA, model guidelines adapted by the
Federation of State Medical Boards also encourage opi-
oid management with proper documentation (138).
3.2 Response to Alleged Undertreatment
The alleged undertreatment of pain as a major
health problem in the United States led to the devel-
opment of initiatives to address the multiple alleged
barriers responsible for the undertreatment of pain.
Consequently, numerous clinical guidelines have been
developed, even though none of them were based on
evidence-based medicine. In 2001, the Joint Commis-
sion on the Accreditation of Healthcare Organizations
(JCAHO) introduced the concept that pain was the
“fifth vital sign,” in an effort to increase the aware-
ness of pain in the hospitalized patient, and by design,
improve the treatment of that pain. Unfortunately,
the current emphasis on pain assessment as the fifth
vital sign has resulted in the potential overmedica-
tion of a group of patients (139). The results of the
effect of JCAHO regulations have been controversial
(140-142). One study showed that opioid adverse drug
reactions increased significantly from 11 to 24.5 per
100,000 inpatient hospital days (140). However anoth-
er study (141) showed increased opioid consumption
without an increase in the length of the stay, increase
in the use of naloxone, or an increase in treatment
for postoperative nausea and vomiting. Yet, another
study (142) showed that routinely measuring pain by
the fifth vital sign did not increase the quality of pain
management.
www.painphysicianjournal.com S13
ASIPP Opioid Guidelines
Multiple reviews (6,9-19) have shown a lack of
consistent effectiveness of opioids in reducing pain
and improving functional status. A cost analysis of
chronic spinal pain (143) suggested that treatment
with medications alone did not significantly improve
a patients’ ability to stand, sit, walk, travel, social-
ize, and work both in and outside the home. How-
ever, complementary treatment components, such
as anesthetic procedures, physical therapy, group
education, and cognitive-behavioral psychotherapy,
seemed to directly affect patients’ pain-related func-
tional impairments. It is argued that physicians should
be encouraged to prescribe opioids because they are
indispensable for the treatment of pain and suffer-
ing, because uncontrolled pain may have deleterious
physical effects, and because persistent pain destroys
peoples’ autonomy, dignity, and decision-making ca-
pacity (6,14,144,145). Thus, the availability of opioids
has skyrocketed dramatically in the past few decades,
partly due to politics and the emotional issues in-
volved with efforts to improve awareness and treat-
ment of chronic pain. Despite equal recognition of the
major side effects drug abuse and addiction by
opponents and equally by proponents, proponents
continue to promote extensive opioid use under the
umbrella of undertreatment of pain, leading to an ex-
plosion in opioid therapy. As a result, most patients
(over 90%) presenting to pain management settings,
and receiving treatment at pain management centers
have been receiving opioids, in spite of problems of
abuse, diversion, and other side effects (120,146-170).
The therapeutic use of opioids has exploded in the
United States, witnessed by increased sales of hydro-
codone by 244% from 1997 to 2006, while methadone
usage increased 1,177% and oxycodone increased
732% (Table 3 and Fig. 1) (5). Coupled with increased
retail sales in therapeutic opioid usage, the pattern of
type of opioid usage also has changed. In 1997, the
most commonly used opioid was codeine, followed by
hydrocodone and oxycodone. However, in 2006, the
most commonly used opioid was oxycodone, followed
by hydrocodone and morphine.
Overall, opioids increased from 50.7 million grams
of medication in 1997 to 115.3 million grams of medi-
cation in 2006, an overall increase of 127% (5). In addi-
tion, the estimated number of prescriptions filled for
controlled substances increased from 222 million in
1994 to 354 million in 2003 (4,171,172). Prescriptions
Table 3. Retail sales of opioid medications (grams of medication), 1997–2006.
Numbers in parenthesis are percentage of change from previous year. * For year 2000, data is not available; the average of 1999 and 2001 was
taken. Source: www.deadiversion.usdoj.gov/arcos/retail_drug_summary/index.html
Adapted from Manchikanti and Singh (5). Therapeutic opioids: A ten-year perspective on the complexities and complications of the escalating
use, abuse, and nonmedical use of opioids. Pain Physician 2008; 11: S63-S88.
Drug 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006
% of
change
from
1997
Methadone 518,737
692,675
(34%)
964,982
(39%)
1,428,840*
(48%)
1,892,691
(32%)
2,649,559
(40%)
3,683,881
(39%)
4,730,157
(28%)
5,362,815
(13%)
6,621,687
(23%)
1177%
Oxycodone 4,449,562
6,579,719
(48%)
9,717,600
(48%)
15,305,913
(58%)
19,927,286
(30%)
22,376,892
(12%)
26,655,152
(19%)
29,177,530
(9%)
30,628,973
(5%)
37,034,220
(21%)
732%
Fentanyl Base 74,086
90,618
(22%)
107,141
(18%)
146,612*
(37%)
186,083
(27%)
242,027
(30%)
317,200
(31%)
370,739
(17%)
387,928
(5%)
428,668
(11%)
479%
Hydromorphone 241,078
260,009
(8%)
292,506
(12%)
346,574*
(18%)
400,642
(16%)
473,362
(18%)
579,372
(22%)
655,395
(13%)
781,287
(19%)
901,663
(15%
274%
Hydrocodone 8,669,311
10,389,503
(20%)
12,101,621
(16%)
14,118,637
(17%)
15,594,692
(10%)
18,822,619
(21%)
22,342,174
(19%)
24,081,900
(8%)
25,803,543
(7%)
29,856,368
(16%)
244%
Morphine 5,922,872
6,408,322
(8%)
6,804,935
(6%)
7,807,511
(15%)
8,810,700
(13%)
10,264,264
(16%)
12,303,956
(20%)
14,319,243
(16%)
15,054,846
(5%)
17,507,148
(16%)
196%
Codeine 25,071,410
26,018,054
(4%)
23,917,088
(-8%)
23,474,865*
(-2%)
23,032,641
(-2%)
22,633,733
(-2%)
21,865,409
(-3%)
20,264,555
(-7%)
18,960,038
(-6%)
18,762,919
(-1%
-25%
Meperidine
(Pethidine)
5,765,954
5,834,294
(1%)
5,539,592
(-5%)
5,494,898*
(-1%)
5,450,204
(-1%)
5,412,389
(-1%)
5,239,932
(-3%)
4,856,644
(-7%)
4,272,520
(-12%)
4,160,033
(-3%)
-28%
Total 50,713,010
56,273,194
(11%)
59,445,465
(6%)
35,962,089.84
(15%)
75,294,939
(11%)
82,874,845
(10%)
92,987,076
(12%)
98,456,163
(6%)
101,251,950
(6%)
115,272,706
(14%)
127%
Pain Physician 2008: Opioids Special Issue: 11:S5-S62
S14 www.painphysicianjournal.com
for controlled substances increased by 154%, com-
pared to the number of prescriptions written for non-
controlled drugs which increased by 57% (173-175). As
a result, the milligram per person use of therapeutic
opioids in the United States increased from approxi-
mately 74 mg in 1997 to 329 mg per person in 2006,
an increase of 347% (Table 4) (5). Fig. 2 illustrates total
prescriptions for selected narcotic analgesics for 2006
(5,176,177). In 2006, there were about 35-fold more
hydrocodone prescriptions, 10-fold more oxycodone
prescriptions, and 2-fold more fentanyl prescriptions
compared to methadone prescriptions. In addition,
Americans, constituting only 4.6% of the world’s pop-
ulation, have been consuming 80% of the global opi-
oid supply, and 99% of the global hydrocodone sup-
ply, along with two-thirds of the world’s illegal drugs
(1-5,178-181).
Multiple authors also have evaluated the increase
in opioid use along with cost and health consequenc-
es which have been increasing substantially over the
years (182-184). The analysis of the National Ambu-
latory Medical Care Survey, using data from 1980 to
1981 and 1999 to 2000, evaluating over 130,000 visits
showed the doubling of opioid use for chronic pain
from 8% to 16% and for acute pain the increase was
from 8% to 11% (182). In addition, the study also
showed that prescriptions for more potent opioids
such as hydrocodone, oxycodone, and morphine in-
creased from 2% to 9% in visits corresponding to 5.9
million visits in 2002 — an increase of 4.6 million visits
from 1980 for chronic musculoskeletal pain. Further,
in the analysis of analgesic use for low back pain and
its impact on health care costs and service use (183),
in 2001, 55.5%of members with claims for low back
services received analgesics costing a total of $1.4 mil-
lion, of which 68% were opioids. Opioid use was also
associated with high volume usage of low back pain
services and correlated with the higher use of opioids
in patients with psychogenic pain and low back pain
related to orthopedic devices such as fusion. There
have been reports of association of opioid use with
increased disability, medical costs, subsequent surgery,
and continued or late opioid use (182-186). Webster
et al (185) showed that patients receiving more than
450 mg equivalent of morphine over a period of sev-
eral months were, on average, disabled 69 days lon-
Fig. 1. The increase in therapeutic opioid use in the United States (grams/100,000 population) from 1997 to 2006.
Source: Based on data from US Drug Enforcement Administration. Automation of Reports and Consolidated Orders System (ARCOS); www.deadiversion.
usdoj.gov/arcos/retail_drug_summary/index.html
Adapted from Manchikanti and Singh (5). Therapeutic opioids: A ten-year perspective on the complexities and complications of the escalating
use, abuse, and nonmedical use of opioids. Pain Physician 2008; 11:S63-S89.
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www.painphysicianjournal.com S15
ASIPP Opioid Guidelines
ger than those who received no early opioids, and also
had 3 times the increased risk for surgery, along with
6 times the increased risk of receiving late opioids.
Greater self-reported disability and poor function was
associated with opioid use (187). Finally, an epide-
miological study from Denmark (188) demonstrated
worse pain, higher health care utilization, and lower
activity levels in opioid treated patients compared to
a matched cohort of chronic pain patients not using
opioids ,suggesting that when opioids are prescribed
liberally, even if some patients benefit, the overall
population does not. Opioids are prescribed liberally
for chronic pain in Denmark. In an evaluation of pri-
mary care patients, the frequency of opioid disorders
was 4 times higher in patients receiving opioid thera-
py compared with general population samples (3.8%
vs 0.9%) (189).
3.3 Prescription Opioids in Chronic Pain
Numerous reviews have critically evaluated
the effectiveness of opioid therapy in chronic pain
(1,6,11-19). In a meta-analysis of opioid use in pa-
tients with chronic low back pain, Martell et al (10)
concluded that opioids do not provide effective pain
relief and do not increase functional status in chron-
ic low back pain. Ballantyne (6), after directly com-
paring the efficacy of different opioids, concluded
that a non-significant reduction in pain was present.
Chou et al (11) concluded there was insufficient and
poor evidence to prove the safety or effectiveness
or any opioids. Kalso et al (12) in their critical anal-
ysis concluded that the mean decrease in pain in-
tensity in most studies was only 30%, whereas only
44% of the patients continued treatment for 7 to
24 months. Furlan et al (13) provided a more som-
ber view of opioids concluding that strong opioids
were more effective with pain relief and functional
outcomes, even though drop-out rates averaged
33%. Two Cochrane reviews (15,16) showed unsat-
isfactory long-term results in managing neuropathic
(15) and nociceptive pain (16). A recent systematic
review and meta-analysis (9) of efficacy and safety
of long-term opioid therapy for chronic non-can-
cer pain concluded that many patients discontinue
long-term opioid therapy due to adverse events or
insufficient pain relief. However, they also conclud-
ed that weak evidence suggests that oral opioids
reduce pain long-term in the relatively small pro-
portion of individuals with chronic non-cancer pain
who continue treatment. Sandoval et al (18) in a sys-
tematic review of methadone found no randomized
trials for long-term use of methadone and showed
only limited evidence with observational reports.
Cepeda et al (17) performed a systematic review
and meta-analysis of randomized clinical trials of tra-
madol and concluded that tramadol is more effec-
tive than placebo for the treatment of osteoarthritis
when the pain is moderate. However, tramadol was
only of limited benefit when the pain was severe.
Overall, the evidence supporting the long-term
analgesic efficacy is weak at best based on the present
evidence. In addition, not surprisingly, epidemiological
Table 4. The increase in therapeutic opioids use in the U.S. (mg/person) from 1997 to 2006.
* For year 2000 data is not available, the average of 1999 and 2001 was taken.
Source: Data taken from U.S. Drug Enforcement Administration. Automation of Reports and Consolidated Orders System (ARCOS); www.deadiversion.usdoj.
gov/arcos/retail_drug_summary/index.html. Access date: 3/13/08
Adapted from Manchikanti and Singh (5). Therapeutic opioids: A ten-year perspective on the complexities and complications of the escalating
use, abuse, and nonmedical use of opioids. Pain Physician 2008; 11:S63-S88.
Type 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006
% of Change
from 1997
Morphine 22.20 24.01 24.50 28.11 31.72 36.95 44.30 51.55 54.20 63.03 184%
Methadone 1.94 2.60 3.47 5.14* 6.81 9.54 13.26 17.03 19.31 23.84 1,129%
Oxycodone 16.68 24.66 34.99 55.11 71.75 80.56 95.97 105.05 110.27 133.33 899%
Hydrocodone 32.49 38.93 43.57 50.83 56.15 67.77 80.44 86.70 92.90 107.49 231%
Fentanyl 0.28 0.34 0.39 0.53* 0.67 0.87 1.14 1.33 1.40 1.54 450%
Total 73.59 90.54 106.92 139.72 167.1 195.69 235.11 261.66 278 329.23 347%
Pain Physician 2008: Opioids Special Issue: 11:S5-S62
S16 www.painphysicianjournal.com
studies while positive with pain are less positive with
regards to function and quality of life and report the
failure of opioids to improve quality of life in chronic
pain patients (20).
3.4 Nonmedical Use of Prescription Drugs
The National Survey on Drug Use and Health of
2006 (190) showed that an estimated 20.4 million or
8.3% of Americans, ages 12 or older were current (past
month) illicit drug users. Among the illicit drugs, psy-
chotherapeutic drugs which include prescription type
pain relievers, tranquilizers, stimulants, and sedatives
are included. Marijuana and hashish are the most
commonly used illicit drugs with 14.8 million current
users, or 6% of the U.S. population. Cocaine was used
by 2.4 million, whereas hallucinogens were used in the
past month by 1 million persons. However, surprisingly,
next to marijuana, 7.0 million (2.8%) persons aged 12
or older had used prescription-type psychotherapeutic
drugs nonmedically in the past month. Of these, 5.2
million had used pain relievers, an increase from 4.7
million in 2005 (Table 5). The categories of nonmedical
use of psychotherapeutics and pain relievers were well
ahead of the illicit drug use of cocaine, hallucinogens,
inhalants, methamphetamine, heroin, and LSD.
The increases for current nonmedical use of psy-
chotherapeutics over a period of the last 10 years
(1997 to 2006) was 162% compared to 33% for mari-
juana and hashish, and 61% for cocaine. Consequent-
ly, psychotherapeutics were the only ones that showed
significant increases from 2002 to 2006, whereas,
marijuana and cocaine were similar over a period of
5 years (5).
Statistics of new initiatives also continue to be
grim with 2.6 million persons aged 12 or older using
psychotherapeutic drugs nonmedically for the first
time within the past year in 2006 (190). Similarly, num-
bers of new users for specific psychotherapeutics in
2006 were 2.2 million for pain relievers, 1.1 million for
tranquilizers, 845,000 for stimulants, and 267,000 for
sedative (Table 6).
Analysis of long-term statistics based on yearly use
of illicit drugs are concerning (5). The past year use of
illicit drugs in 2006 was 35.77 million or 4.5% of the
population, whereas nonmedical use of psychothera-
peutics for the past year in the 2006 survey was 16.287
Fig. 2. Total prescriptions of selected narcotic analgesics (29).
Source: Methadone Morality Working Group Drug Enforecement Administration, Office of Diversion Control.
Adapted from Manchikanti and Singh (5). Therapeutic opioids: A ten-year perspective on the complexities and complications of the
escalating use, abuse, and nonmedical use of opioids. Pain Physician 2008; 11:S63-S88.
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www.painphysicianjournal.com S17
ASIPP Opioid Guidelines
million compared to 15.172 million in 2005 and 14.643
million in 2004, or 6.6% of the population aged 12 or
older in 2006, 6.2% in 2005, and 6.1% in 2004 with
significant increases (Table 7). Similarly, lifetime use
of psychotherapeutics drugs has been increasing over
the years with nonmedical use of psychotherapeutic
increasing from 20% of the population in 2005 to
20.3% in 2006 or almost 50 million. A review of thera-
peutic opioids with a 10-year perspective on the com-
plexities and complications of escalating use, abuse,
and nonmedical use of opioids describes in detail the
issues related to therapeutic opioid abuse (5).
A survey of American adults by USA Today and
HBO (192) in 2006 found that:
One in 5 adults have a close relative who is or was
addicted to drugs or alcohol.
Three-quarters of American adults who have a
family member suffering from the disease of drug
or alcohol addiction think addiction is a disease.
Emotional and Devastating/Horrible are the words
that were most often used to describe the effects
of a family member's addition.
Almost one of 10 of those who say a family mem-
ber’s addiction has had a major negative impact
on their financial situation say they have had to
take out a loan or run up credit card bills as a di-
rect result of this addiction.
About a fifth of those who say a family member’s
addiction has had a major negative impact on
their marriage, family relationships, or emotional
health say they sought professional counseling.
One third of American adults who have a family
member suffering from the disease of drug or al-
cohol addiction say the addiction has caused es-
trangement among family members.
Almost half of U.S. adults who have a family
Table 5. Types of illicit drug use in the past month among persons aged 12 or older: Numbers in thousands, from 1997 to 2006.
-- Not available.
a Difference between estimate and 2006 estimate is statistically significant at the 0.05 level.
b Difference between estimate and 2006 estimate is statistically significant at the 0.01 level.
c Difference between estimate and previous year estimate is statistically significant at the 0.01 level.
1 Illicit drugs include marijuana/hashish, cocaine (including crack), heroin, hallucinogens, inhalants, or prescription-type psychotherapeutics used nonmedically.
2 Nonmedical use of prescription-type psychotherapeutics includes the nonmedical use of pain relievers, tranquilizers, stimulants, or sedatives, and does not
include over-the-counter drugs.
Source: SAMHSA, Office of Applied Studies, National Survey on Drug Use and Health, 1995 to 2006.
Adapted from Manchikanti and Singh (5). Therapeutic opioids: A ten-year perspective on the complexities and complications of the escalating
use, abuse, and nonmedical use of opioids. Pain Physician 2008; 11: S63-S88.
Drugs 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006
% change
from 1997
to 2006
Nonmedical Use of
Psychotherapeutics
2
2,665
(1.2%)
2,477
(1.1%)
3,952
(1.8%)
3,849
(1.7%)`
4,811
c
(2.1%)
6,210
a
(2.6%)
6,336
(2.7%)
6,007
b
(2.5%
b
)
6,405
(2.6%)
6,991
(2.8%)
162%
Pain Relievers
-- --
2,621
(1.2%)
2,782
(1.2%)
3,497
c
(1.6%)
4,377
b
(1.9%
a
)
4,693
(2.0%)
4,404
b
(1.8%
a
)
4,658
a
(1.9%)
5,220
(2.1%)
NA
OxyContin®
-- -- -- -- -- -- --
325
(0.1%)
334
(0.1%)
276
(0.1%)
NA
Tranquilizers
845
(0.4%)
655
(0.3%)
1,097
(0.5%)
1,000
(0.4%)
1,358
c
(0.6%)
1,804
(0.8%)
1,830
(0.8%)
1,616
(0.7%)
1,817
(0.7%)
1,766
(0.7%)
109%
Stimulants
612
(0.3%)
633
(0.3%)
950
(0.4%)
788
(0.4%)
1,018
(0.5%)
1,218
(0.5%)
1,191
(0.5%)
1,189
(0.5%)
1,067
(0.4%)
1,191
(0.5%)
95%
Sedatives
187
(0.1%)
210
(0.1%)
229
(0.1%)
175
(0.1%)
306
(0.1%)
436
(0.2%)
294
(0.1%)
265
(0.1%)
272
(0.1%)
385
(0.2%)
106%
Marijuana and
Hashish
11,109
(5.1%)
11,016
(5.0%)
10,458
(4.7%)
10,714
(4.8)
12,122
c
(5.4%)
14,584
(6.2%)
14,638
(6.2%)
14,576
(6.1%)
14,626
(6.0%)
14,813
(6.0%)
33%
Cocaine
1,505
(0.7%)
1,750
(0.8%)
1,552
(0.7%)
1,213
(0.5%)
1,667
c
(0.7%)
2,020
a
(0.9%)
2,281
(1.0%)
2,021
a
(0.8%)
2,397
(1.0%)
2,421
(1.0%)
61%
Total Illicit Drugs
1
13,904
(6.4%)
13,615
(6.2%)
13,829
(6.3%)
14,027
(6.3%)
15,910
c
(7.1%)
19,522
(8.3%)
19,470
(8.2%)
19,071
a
(7.9%)
19,720
(8.1%)
20,357
(8.3%)
46%
Pain Physician 2008: Opioids Special Issue: 11:S5-S62
S18 www.painphysicianjournal.com
Note: 2002 to 2006 data is based on 2006 National Survey on Drug Use and Health Survey Report.
NOTE: Past year initiates are defined as persons who used the substance(s) for the first time in the 12 months prior to date of interview.
a Difference between estimate and 2006 estimate is statistically significant at the 0.05 level.
2 Nonmedical use of prescription-type psychotherapeutics includes the nonmedical use of pain relievers, tranquilizers, stimulants, or sedatives, and does not
include over-the-counter drugs.
Source: SAMHSA, Office of Applied Studies, National Survey on Drug Use and Health, 2002, 2003, 2004, 2005, and 2006.
Adapted from Manchikanti and Singh (5). Therapeutic opioids: A ten-year perspective on the complexities and complications of the escalating use,
abuse, and nonmedical use of opioids. Pain Physician 2008; 11:S63-S88.
Drugs 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006
% change
from 1997
to 2006
Pain Relievers
2
1,316 1,548 1,810 2,268 2,400 2,320 2,456
a
2,422
a
2,193 2,150 63%
Tranquilizers 668 860 916 1,298 1,212 1,184 1,071 1,180 1,286 1,112 66%
Stimulants 553 648 706 808 853 783 715 793 647
a
845 53%
Sedatives 120 147 164 191 225 209 194 240 247 267 123%
Marijuana 2,603 2,498 2,640 2,746 2,793 2,196 1,973 2,142 2,114 2,063 -21%
Cocaine 861 868 917 1,002 1,140 1,032 986 998 872 977 13%
Heroin 114 140 121 114 154 117 92 118 108 91 -20%
Table 6. Past year initiates for illicit drugs from 1997 to 2006 (numbers in thousands).
Table 7. Types of illicit drug use in the past year among persons aged 12 or older from 1997 to 2006 (numbers in thousands).
Note: 2002 to 2006 data is based on 2006 National Survey on Drug Use and Health Survey Report.
Figures in ( ) indicate percentage.
-- Not available.
a Difference between estimate and 2006 estimate is statistically significant at the 0.05 level. b Difference between estimate and 2006 estimate is statistically
significant at the 0.01 level. c Estimate is statistically different than previous year 1 Illicit drugs include marijuana/hashish, cocaine (including crack), heroin,
hallucinogens, inhalants, or prescription-type psychotherapeutics used nonmedically. 2 Nonmedical use of prescription-type psychotherapeutics includes the
nonmedical use of pain relievers, tranquilizers, stimulants, or sedatives, and does not include over-the-counter drugs.
Source: SAMHSA, Office of Applied Studies, National Survey on Drug Use and Health, 1995 to 2006.
Adapted from Manchikanti and Singh (5). Therapeutic opioids: A ten-year perspective on the complexities and complications of the escalating
use, abuse, and nonmedical use of opioids. Pain Physician 2008; 11:S63-S88.
Drugs 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006
% change
from 1997
to 2006
Nonmedical Use of
Psychotherapeutics
2
6,111
(2.8%)
5,759
(2.6%)
9,220
(4.2%)
8,761
(3.9%)
11,102
c
(4.9%
c
)
14,680
b
(6.2%)
14,986
b
(6.3%)
14,643
b
(6.1%
b
)
15,172
a
(6.2%
a
)
16,287
(6.6%)
167%
Pain Relievers
-- --
6,582
(3.0%)
6,466
(2.9%)
8,353
c
(3.7%
c
)
10,992
b
(4.7%
b
)
11,671
a
(4.9%)
11,256
b
(4.7%
b
)
11,815
a
(4.9%)
12,649
(5.1%)
NA
OxyContin®
-- -- -- -- -- -- --
1,213
(0.5%)
1,226
(0.5%)
1,323
(0.5%)
NA
Tranquilizers
2,122
(1.0%)
1,940
(0.9%)
2,728
(1.2%)
2,731
(1.2%)
3,673
c
(1.6%
c
)
4,849
(2.1%)
5,051
(2.1%)
5,068
(2.1%)
5,249
(2.2%)
5,058
(2.1%)
138%
Stimulants
1,687
(0.8%)
1,489
(0.7%)
2,291
(1.0%)
2,112
(0.9%)
2,486
c
(1.1%)
3,181
(1.4%)
2,751
b
(1.2%
a
)
2,918
a
(1.2%)
2,771
b
(1.1%
b
)
3,394
(1.4%)
101%
Sedatives
638
(0.3%)
522
(0.2%)
631
(0.3%)
611
(0.3%)
806
(0.4%)
981
(0.4%)
831
(0.3%)
737
(0.3%)
750
(0.3%)
926
(0.4%)
45%
Marijuana and
Hashish
19,446
(9.0%)
18,710
(8.6%)
19,102
(8.6%)
18,589
(8.3%)
21,086
c
(9.3%
c
)
25,755
(11.0%
a
)
25,231
(10.6%)
25,451
(10.6%)
25,375
(10.4%)
25,378
(10.3%)
31%
Cocaine
4,169
(1.9%)
3,811
(1.7%)
3,742
(1.7%)
3,328
(1.5%)
4,186
c
(1.9%
c
)
5,902
(2.5%)
5,908
(2.5%)
5,658
(2.4%)
5,523
(2.3%)
6,069
(2.5%)
46%
Total Illicit Drugs
1
24,189
(11.2%)
23,115
(10.6%)
25,402
(11.5%)
24,535
(11.0%)
28,409
c
(12.6%
c
)
35,132
(14.9%)
34,993
(14.7%)
34,807
(14.5%)
35,041
(14.4%)
35,775
(14.5%)
48%
www.painphysicianjournal.com S19
ASIPP Opioid Guidelines
member suffering from the disease of drug or
alcohol addiction say their family member has
never sought treatment. Of those whose family
member has sought treatment, 3 out of 10 only
sought treatment after intervention.
Of those whose family member sought treatment,
almost half say the family member relapsed and
almost one out of 10 say there was no improve-
ment at all.
Only 3 out of 10 respondents say their addicted
family member consulted with a medical doctor
or other medical professional specializing in the
treatment of addiction.
Over half of the respondents say their addicted
family member was never evaluated for psycho-
logical illness.
The latest Center on Addiction and Substance
Abuse (CASA) report (193) also presented alarming
statistics finding that at 11 million high school stu-
dents (80%) and 5 million middle school students
(44%) attended drug-infested schools, where they
have personally witnessed illegal drug use, illegal
drug dealing, and students high on the grounds of
the school. More than one in 3 (37%) teens say they
can buy marijuana within a day, and 17% say they can
buy marijuana within an hour. Even more concerning,
students who identify themselves as “popular” and
attended a drug-infested school, were 5 times more
likely to get drunk in a typical month, and are much
more likely to abuse prescription and illegal drugs. It
is particularly concerning that 28.9% of pharmacists
have been robbed within the past 5 years, and 20.9%
no longer stock certain controlled drugs in order to
prevent future robberies.
3.4.1 Physician Survey Highlights
In a 2006 survey (194) of 248 primary care phy-
sicians (PCP) regarding their attitudes toward the
prescribing of opioids for chronic pain, their major
concerns included prescription drug abuse (84.2%),
addiction (74.9%), adverse effects (68%), tolerance
(60.7%), and medication interaction (32%). A majority
were comfortable prescribing opioids for cancer pain,
but they were less comfortable prescribing opioids
for back pain or for patients with a history of drug or
alcohol abuse. Only 6.9% reported obtaining a urine
screen prior to initiating opioid therapy, and only
15% performed urine screens on patients currently on
opioids.
Similarly, in another survey (195) of 111 primary
care attendings, residents, and nurse practitioners in
8 community clinics, the PCPs reported that 37.5% of
their adult patients in a given week had chronic pain
issues. But, they attributed these problems with pain
care to patient related factors such as self-manage-
ment and abuse issues instead of provider or practice
system factors.
In a study published in 2007 (196) evaluating
long-term opioid contract use for chronic pain man-
agement in primary care practice, illustrating a 5-year
experience, contracts were discontinued in approxi-
mately 40% of the patients. However, only 17% were
cancelled for substance abuse and noncompliance
and 20% discontinued the contract voluntarily. In this
population, urine toxicology screens were obtained in
42% of patients of whom 38% were positive for illicit
substances. This report reveals a lack of a systematic
approach to opioid administration and monitoring
in primary care practices. In another article, it was
questioned with regards to the dilemmas experienced
when prescribing opioids in general practice (197).
There have also been publications with regards to
designing a primary care-based chronic pain manage-
ment program from a scientific basis (198) and guid-
ance for contractual approaches (198). Further, issues
related to chronic pain patients, adherence monitor-
ing, etc., have been described in detail in chronic pain
management settings (1).
A CASA survey of 979 physicians regarding the
diversion and abuse of controlled prescription drugs
showed that physicians perceive the 3 main mecha-
nisms of diversion to be doctor shopping, patient de-
ception, or manipulation of doctors, and forged or
altered prescriptions (180). Further, a good majority of
physicians believe that patients account for the bulk
of the diversion problem. In addition, less than 20% of
surveyed physicians received any medical school train-
ing in identifying prescription drug diversion, and less
than 40% received any training in medical school in
identifying prescription drug abuse and addiction.
It was also shown that 43% of physicians do not ask
about prescription drug abuse when taking a patient’s
health history and over 70% of physicians have re-
frained from prescribing controlled drugs due to con-
cerns that a patient may become addicted to them.
3.4.2 Pharmacist Survey Highlights
There have been no new studies of pharmacists
since the CASA study of 2005 (180). At that time,
28.4% of pharmacists did not regularly validate the
prescribing physician’s DEA number when dispensing
controlled drugs; one in 10 (10.5%) rarely or never do
Pain Physician 2008: Opioids Special Issue: 11:S5-S62
S20 www.painphysicianjournal.com
so. Sixty-one percent did not regularly ask if the pa-
tient is taking any other controlled drugs, 25.8% rare-
ly or never do. Seventy-eight percent become “some-
what or very” concerned about diversion or abuse
when a patient asks for a controlled drug by name;
83.1% have refused to dispense a controlled drug in
the past year because of suspicions of diversion; and
51.8% believed that patients account for the bulk of
the diversion problems.
3.4.3 Drug Abuse Warning Network (DAWN) Reports
The Drug Abuse Warning Network (DAWN) (199)
examined the involvement of opiates and deaths re-
lated to drug misuse. Nearly 1.3 million emergency
department (ED) visits in 2005 were associated with
drug misuse/abuse (200). Nonmedical use of pharma-
ceuticals was involved in nearly a half million of these
ED visits with opioids constituting over 196,000 visits
(an increase over 2004 of 24%). There was a 92% in-
crease in visits due to hydromorphone products (most
likely due to Palladone overdoses), and a 29% increase
in methadone visits. Two-thirds or more of ED visits
associated with opiates/opioids, benzodiazepines, and
muscle relaxants involved multiple drugs, and alco-
hol was one of the other drugs in about a quarter of
such visits. Toxic effects were reported in 10% of visits.
The DAWN data also showed that opioids account for
more overdose deaths in the United States than either
heroin or cocaine.
In 2006, young adults aged 18 to 25 demonstrat-
ed rates of current use of illicit drugs to be higher
(19.8%) than for youths aged 12 to 17 and adults aged
26 or older, with 16.3% using marijuana, 6.4% using
psychotherapeutics nonmedically, 2.2% using cocaine,
and 1.7% using hallucinogens (Fig. 3).
3.4.4 Healthcare and Social Costs
Unfortunately, the current emphasis on pain as-
sessment as the fifth vital sign has resulted in the
potential overmedication of a group of patients
(139,140). Prescription drug abuse inflicts enormous
costs on our society. The mortality from opioids can-
not be ignored (201,202). In a study of the Centers for
Disease Control (CDC) (203), increasing deaths were
found from opioid analgesics in the United States. Un-
intentional drug poisoning mortality rates increased
an average of 5.3% per year from 1979 to 1990 and
18.1% per year from 1990 to 2002. The rapid increase
during the 1990s reflects the rising number of deaths
attributed to opioids and unspecified drugs. Between
1999 and 2002 (the last date for which the informa-
tion is available), the number of opioid analgesic poi-
sonings on death certificates increased 91.2%, while
heroin and cocaine poisonings increased 12.4% and
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Fig. 3. Past month use of selected illicit drugs among young adults aged 18 to 25: 2002 – 2006 (1).
www.painphysicianjournal.com S21
ASIPP Opioid Guidelines
22.8%, respectively. In 2002, opioid analgesic poison-
ing was listed in 5,528 deaths – more than either her-
oin or cocaine. The follow-up evaluation in 2007 (200)
revealed that unintentional drug poisoning was sec-
ond only to motor vehicle crashes as a cause of death
from unintentional injury in the United States. This
updated study showed the number of unintentional
poisoning deaths increased from 12,186 in 1999 to
20,950 in 2004, with an increase of age-adjusted rate
of 62.5% from 4.4 per 100,000 population in 1990 to
7.1 in 2004. The highest rate of deaths (59.6) in 2004
were among persons aged 35 to 54 years. Among the
opioids, methadone has been implicated in more un-
intentional poisoning deaths than any other opioid
(176,177,204-207).
Methadone-related deaths from 1999 to 2004 in-
creased 390%, whereas the number of all poisoning
deaths increased 54% (203). In addition, methadone
mentions in poisoning deaths increased from 4% of all
poisoning deaths to 13% of all poisoning deaths. The
increase in methadone deaths was 29% from 2002 to
2004, in contrast to all poisoning deaths of 6% during
the same period (Table 8). Further, persons aged 15 to
24 years contributed to the largest increases of deaths
with a rate of 11 times to that of 99 in 2004, even
though most methadone deaths were in persons aged
35 to 44 and 45 to 54 years of age. However, reassess-
ment of methadone mortality in 2007 also showed in-
creasing use, misuse, diversion, and abuse (208,209).
This led to a stricter warnings about methadone by
the FDA (210).
3.5 Substance Abuse in Chronic Pain
The central question when prescribing opioids for
chronic, non-cancer pain is how best to balance the
risk of opioid abuse with the pain relief provided by
these medications (7,159).
A prospective cohort study of 196 opioid treated,
chronic, non-cancer pain patients identified predictors
of opioid misuse (160). Misuse was defined as having:
negative urine toxicologic screen (UTS) for prescribed
opioids, UTS positive for controlled substances not
prescribed, procurement of opioids from multiple pro-
viders, diversion of opioids, prescription forgery, or,
UTS positive for stimulants. The strongest predictors
of misuse were the self-reported histories of previous
alcohol or cocaine abuse, or previous criminal drug
or alcohol-related convictions. Demographics such as
gender, race, literacy, disability, and socioeconomic
status were not associated with misuse.
The Veterans Administration looked at longitu-
dinal administrative data from 2000 to 2005 (15,000
patients), and found that nonopioid substance abuse
(such as alcohol) was the strongest predictor of opi-
oid abuse (211). Mental health disorders were mod-
erately strong predictors; the incidence of mental
health disorders was much higher than the prevalence
of nonopioid substance abuse (45.3% vs 7.6%), sug-
gesting that mental health disorders were indicative
of a higher risk. Males, younger adults, and individuals
with greater days supply of prescription opioids were
more likely to develop opioid abuse. To look at the
issue from the other side, a representative sample of
Table 8. Number of poisoning deaths in which specific narcotic substances are mentioned, 1999 to 2004.
Substance 1999 2000 2001 2002 2003 2004
1999-2004
% change
2003-2004
% change
Poisoning by all Narcotics and
Psychodysleptics
9,995 10,173 11,480 14,247 15,731 16,735 68.1 6.4
Opium 4 2 5 3 4 1 -75.0 -75.0
Heroin 1,964 1,846 1,782 2,091 2,080 1,881 -4.2 -9.6
Other Opioids 2,757 2,932 3,484 4,431 4,877 5,242 90.1 7.5
Methadone 786 988 1,456 2,360 2,974 3,849 389.7 29.4
Other Synthetic Narcotics 732 784 962 1,301 1,406 1,668 127.9 18.6
Cocaine 3,832 3,565 3,840 4,612 5,212 5,461 42.5 4.8
Other Narcotics 2,902 2,880 2,881 3,143 3,117 2,761 -4.9 -11.4
Cannabis 37 41 37 50 61 99 167.6 62.3
LSD 3 3 2 0 1 1 -66.7 0.0
Other 9 8 7 5 6 5 -44.4 -16.7
Note: Substance-specific data are not additive because of death.
Source: National Center for Health Statistics, National Vital Statistics System
Pain Physician 2008: Opioids Special Issue: 11:S5-S62
S22 www.painphysicianjournal.com
390 patients from 2 methadone maintenance treat-
ment programs (MMTP) reveled that 37% of these
patients suffered from severe, chronic pain (212). Cor-
relates of chronic pain included age (odds ratio [OR]
2.08), chronic illness (OR 1.88), and lifetime psychiatric
illness (OR 1.77).
Fleming et al (189) in a sample of primary care
patients found that the frequency of opioid use dis-
orders was 4 times higher in patients receiving opi-
oid therapy compared to nonopioid therapy patients.
They also showed that DSM-IV evidence of opioid use
disorder was seen in 9.7% of patients, 4 times higher
than the reported general population, and 24% of
urine drug testings were positive for illicit drugs.
Even though occasional studies (213) and pro-
ponents claim extremely low levels of opioid abuse,
opioids are by far the most abused drugs, especially
in chronic pain management settings. Numerous in-
vestigations have illustrated drug abuse in 18% to
41% in patients receiving opioids for chronic pain
(1-5,10,146-163,214-216).
Martell et al (10) in a systematic review of opioid
treatment for chronic back pain, estimated the prev-
alence of lifetime substance use disorders to range
from 36% to 56%, with a 43% current substance use
disorder rate. Further, aberrant medication-taking be-
haviors ranged from 5% to 24%.
The abuse of drugs in chronic pain patients may
also include illicit drugs in conjunction with controlled
substances. Multiple investigators have studied the is-
sue of illicit drug use in chronic pain patients receiving
controlled substances (146,158,160-163). The results
showed that illicit drug use in patients without con-
trolled substance abuse was found in 14% to 16% of
patients and illicit drug use in patients with controlled
substance abuse was present in 34% of the patients
(148,150,151). Illicit drug use was significant in chronic
pain patients in general, but illicit drug use was simi-
lar in patients using either long-acting or short-acting
opioids (161). In other evaluations, it was shown that
adherence monitoring will in fact decrease controlled
substance abuse and illicit drug use (158,163).
Along with the increase of prescriptions for
controlled drugs from 1992 to 2002 of 154% (173-
175,215-218), there was also a 90% increase in the
number of people who admitted abusing controlled
prescription drugs (219). Studies also evaluated opioid
abuse in the insured population of the United States
(218). Opioid abuse was determined to be present in
6.7 to 8 per 10,000 persons insured however, opioid
abusers presented with multiple comorbidities and ex-
penses 8 times higher than for non-abusers ($15, 884
vs $1,830).
3.6 Economic Impact
The cost of opioid abuse is enormous ranging as
high as $300 billion a year as per the estimates of the
White House Budget Office. The White House Office
of National Drug Control Policy, a component of the
Executive Office of the President, established by the
Anti-Drug Abuse Act of 1990, has been spending $12
to $13 billion each year (2).
A study by the Office of Management and Bud-
get estimated drug abuse costs to the United States
at $300 billion a year, including government anti-drug
programs and the costs of crime, healthcare, accidents,
and lost productivity. In the Aid to Family with Depen-
dent Children (AFDC), Medicaid and food stamp pro-
grams, the incidence of drug abuse varies from 9.4%
to 16.4% (218).
3.7 Drug Diversion
Drugs can be diverted from their lawful purpose
to illicit use at any point in the pharmaceutical manu-
facturing and distribution process. The diversion of
prescription drugs among adults is typically described
to occur through one of the following: doctor shop-
ping, illegal internet pharmacies, drug theft, prescrip-
tion forgery, and illicit prescriptions by physicians.
Youths typically acquire drugs by stealing from their
relatives or buying from classmates who sell their le-
gitimate prescriptions.
For the SAMHSA surveys (190,191), nonmedical us-
ers of prescription-type psychotherapeutic drugs were
asked questions regarding how they obtained the
drugs they recently used nonmedically. In both 2005
and 2006, over half of the nonmedical users of pre-
scription-type pain relievers, tranquilizers, stimulants,
and sedatives said they obtained the drugs they used
most recently “from a friend or relative for free.” A
follow-up question added in 2006 asked these respon-
dents where their friend or relative had obtained the
drugs. In 80.7% of the cases, the individuals indicated
that their friend or relative had obtained the drugs
from just one doctor. Only 1.6% reported that the
friend or relative had bought the drug from a drug
dealer or other stranger (Fig. 4).
As long as long-acting forms of opioids can be
converted into rapid-onset drugs, there will be a
push to divert and abuse these medications (221). In
www.painphysicianjournal.com S23
ASIPP Opioid Guidelines
the wake of the OxyContin abuse scandals, the FDA
has added warning labels to extended release formu-
lations, admonishing against crushing and chewing
tablets, which may have led to increased experimen-
tation and abuse (222). The ease with which an active
ingredient can be extracted form the parent medi-
cation has been seen as related to the medication’s
abuse potential; unfortunately, the pharmacy indus-
try currently lacks standards to assess the tamper-re-
sistance of a formulation, which makes it difficult to
compare different formulations from different man-
ufacturers. Katz and colleagues (223) have proposed
4 components of extractability: ease of extraction,
purity of extract, efficiency of extraction, and poten-
cy of extract. They then developed a rating system,
but concluded that more work needed to be done
on the system before it could be used as an industry
standard.
Doctor shopping by drug abusers is one of the
most common ways of getting illegal controlled sub-
stances (224). Generally, this term refers to the visit by
an individual—who may or may not have legitimate
medical needs—to several doctors, each of whom
writes a prescription for a controlled substance. The
individual will visit several pharmacies, receiving more
of the drug than intended by any single physician, typ-
ically for the purpose of feeding an addiction. Other
illegal activities may include forged prescriptions and
“pill mills” (facilities that prescribe large volumes of
opioids without legitimate purpose, often for cash).
Illegal internet pharmacies have been available
since about 1999. MarkMonitor, a company that ana-
lyzes online brands, estimates that consumers may be
spending $4 billion annually on prescription medicines
at uncertified online websites linked to spam emails
(225). Of the 3,160 sites identified in the report, a
third are ranked by the Alexa website tracking service
as high volume sites and had an average of 32,000 visi-
tors a day. MarkMonitor estimated that if just 0.5% of
customers purchased on average $70 worth of medi-
cations, these ranked sites alone would earn $4 billion
a year.
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1
The Other category includes the sources: “Wrote Fake Prescription,” “Stole from Doctors Office/Clinic/Hospital/Pharmacy,” and “Some
Other Way.”
Fig.4. Where pain relievers were obtained for most recent nonmedical use among past year users aged 12 or older: 2006 (1).
Source: Abuse and Mental Health Services Administration (2007) (190). Results from the 2006 National Survey on Drug Use and Health:
National Findings.
Pain Physician 2008: Opioids Special Issue: 11:S5-S62
S24 www.painphysicianjournal.com
3.8 Controlling Diversion and Abuse
For nearly 100 years, the laws governing the pre-
scribing of medications with addictive potential (as de-
scribed in the Harrison Narcotics Act of 1914) worked
relatively well to control the access of these medi-
cines while at the same time controlling their misuse.
However, recent technologic developments, such as
internet prescribing, have loosened the controls and
increased the rate of diversion and abuse (226).
3.8.1 Drug Enforcement Administration
The Drug Enforcement Adminstration (DEA), as
an agency within the United States Department of
Justice, is the lead federal law enforcement agency re-
sponsible for enforcing the Controlled Substance Act
(CSA). In cooperation with state authorities and other
federal agencies, the DEA is responsible for prevent-
ing the diversion of controlled substances for illicit
purposes. However, the DEA must comply with inter-
national treaties to the extent that they are not in con-
flict with constitutional provisions; it must also work
closely with foreign, state, and local governments.
The DEA has increased its monitoring of internet pre-
scription drug sales. DEA investigations, enforcement,
and intelligence programs have started to work more
closely with other federal, state, and local agencies to
target individuals and organizations involved in diver-
sion and abuse of controlled prescription drugs.
High-profile arrests and prosecutions focus phy-
sicians’ attention on the risks entailed in prescribing
controlled substances in general, and have the specific
effect of increasing physicians’ and pharmacists’ reluc-
tance to prescribe, stock, or dispense opioid analgesics
(227). However, a study published in 2006 looked at
DEA arrest records in an effort to gauge the actual risk
of DEA action (228). The review of the arrests and ad-
ministrative actions of the DEA during fiscal year 2003
and 2004 showed that of the 963,385 physician regis-
trants, there were 557 investigations with 6 civil fines,
22 letters of admonition, 21 administrative hearings,
34 license revocations, and 45 arrests.
3.8.2 State Laws and Regulations
Neither the DEA nor the federal government has
the authority to regulate medical practice; this is the
sole responsibility of the state government. States
can require that a drug prescription be filled within a
specified amount of time after it is written, and they
can classify drugs at a higher level of abuse risk than
the CSA schedule or place the drug on a state con-
trolled substance list if not on the CSA list. State poli-
cies may conflict with or hamper the implementation
of current treatment guidelines for the management
of pain by limiting the amounts of opioid medications
that can be prescribed, requiring special government-
issued prescription forms, using outdated terminol-
ogy, considering opioids only as the treatment of last
resort, and suggesting incorrectly that the therapeu-
tic use of opioids hastens death (229). State medical
boards can address physician concerns about regula-
tory scrutiny and promote the balance between opi-
oid benefits and risks. Before 1989, only a few state
medical boards developed policies governing the use
of controlled substances (230). Since then, 41 states
have adopted such policies, which include regulations
that have the force of law, as well as guidelines and
policy statements.
3.8.3 Prescription Drug Monitoring Programs
States began to address the misuse and abuse of
prescription medications in the 1940s by creating pro-
grams to monitor the dispensing of prescription drugs
(3). These early programs required physicians to use
special multiple-copy, 2- or 3-part prescription order
forms, with a copy sent to a state monitoring program,
and they only monitored Schedule II drugs. By 1999, 15
states had adopted prescription drug monitoring pro-
grams; but they were quite diverse. By the 1990s some
programs were able to initiate electronic reporting, but,
paper or electronic, most still used a variety of triggers
such as number of prescriptions written or volume of
medications prescribed to “flag” physicians or patients
for further investigation. Kentucky established the
Kentucky All Scheduled Prescription Electronic Report-
ing program (KASPER), an effective program that was
limited by the 7 border states that surround Kentucky,
allowing patients to take their prescriptions across state
lines to thwart the program.
President Bush signed the National All Scheduled
Prescription Electronic Reporting (NASPER) Act on
August 11, 2005, making it the only statutorily autho-
rized program to assist states in combating prescrip-
tion drug abuse of controlled substances through a
PDMP, and authorizing the U.S. Department of Health
and Human Services (HHS) to award grants to States to
construct prescription drug monitoring programs (PD-
MPs) and enhance communications between existing
ones. Unfortunately, funding has not been provided
for this activity (3).
A review of monitoring opioid adherence in
chronic pain patients describes PDMPs (159). However,
the effect and effectiveness of PDMPs is difficult to as-
certain. The Medical Expenditure Panel survey showed
www.painphysicianjournal.com S25
ASIPP Opioid Guidelines
an effect from prescription drug monitoring programs
on opioid prescriptions with 3% of people in a non-
PDMP state purchased at least one Schedule II anal-
gesic, compared to 1.6% in states that had a PDMP.
A number of techniques, instruments, and tools have
been described to monitor controlled substance use
and abuse (159). Even though multiple factors may be
involved in drug misuse and abuse, no single instru-
ment or assessment method has universal evaluative
or predictive utility. Thus, multiple techniques and
tools are available, and have been used to monitor ad-
herence. These include various screening tests, urine
drug testing, and prescription monitoring programs.
Each of these methods have some relative validity and
utility in assessing patterns of drug use, misuse, abuse,
and/or the potential occurrence of addiction. Conse-
quently, it is important for the clinician to determine
whether to assess compliance, misuse, abuse, and/or
addiction, so that the appropriate evaluative methods
can be employed.
4.0 PharmacologIcal consIderatIons
Opioids are analgesics compounds that attach to
and modulate ascending and descending pain relat-
ed pathways (231). Opioids may be classified by their
function as agonists, mixed agonists-antagonists, or
antagonists, and by their actions at opioid receptors,
mu, kappa, and delta (231,232). Compounds can have
differing degrees of affinity and efficacy at these vari-
ous receptors (233).
4.1 Opioid Pharmacology
Opiates are naturally occurring alkaloids, such as
morphine from the opium poppy seed. Opioid is the
term used broadly to describe all compounds that ex-
ert activity at the opioid receptor. The term narcotic
derives from the Greek word for stupor (227).
4.1.1 Opioid Receptors
There are opioid receptors within the central ner-
vous system as well as throughout the peripheral tissues.
These receptors are normally stimulated by endogenous
peptides (endorphins, enkephalins, and dynorphins)
produced in response to noxious stimulation. In addi-
tion, peripherally acting opioids (234) and combination
of opioid analgesics have been described (235). Table 9
provides opioid receptors, related indigenous peptides,
agonists, agonist/antagonist, and antagonists.
The opioid receptors were discovered in 1972, and
the first endogenous opioid (enkephalin) was discov-
ered in 1975. Their location in the CNS allows them to
function as neurotransmitters, altering hormone secre-
tion, thermoregulation, and cardiovascular control.
Opioids are classified by their action. These agents
exhibit varying degrees of receptor affinity and effi-
cacy, and can be pure agonist, agonist/antagonist, or
antagonist.
Pure opioid agonists (e.g., morphine, hydromor-
phone, fentanyl) stimulate mu receptors and are the
most potent analgesics. As the dose is increased, an-
algesia occurs in a log linear fashion; the degree of
analgesia induced is limited only by intolerable dose-
related adverse effects. Partial agonists and agonist/
antagonists (example, nalorphine) exhibit a ceiling ef-
fect on the degree of analgesia that they can produce.
Antagonists, as the name implies, counteracts effects
at the opioid receptor.
4.1.2 Opioid Categories
The DEA classifies opioids into schedules related
to potential abuse, and not potency (Table 10).
There has been concern that the lower scheduled
opioids (Schedule III and IV) might have a higher ad-
dictive potential than some of the higher scheduled
opioids (Schedule II). In a recent study (236), it was
suggested that shorter-acting opioids had a lower po-
tential for abuse. They looked at 140 patients on long-
acting opioids (Schedule II) compared to 687 patients
on short-acting opioids and 225 patients on nonopi-
oids. More of the long-acting opioid patients (38%)
were discharged from the practice for non-compliance
compared to the short-acting opioid patients (32%)
or the nonopioid patients (30%). In another study
(161) in an interventional pain management setting
evaluating the abuse of prescription and illicit drugs
in chronic pain patients receiving either short-acting
(hydrocodone) or long-acting (methadone), they con-
cluded that prescription drug abuse as well as illicit
drug use was similar in both groups of patients.
4.1.3 Opioid Metabolism
Many of the side effects of opioids, as well as their
effects, may be related to the opioid metabolites.
Most of the metabolism of opioids occurs in the liver.
The CYP450 enzymes are a super-family of heme-con-
taining, microsomal drug-metabolizing enzymes that
are important in the biosynthesis and degradation of
a wide variety of endogenous compounds, chemicals,
toxins, and medications. More than 2,700 individual
members of the CYP450 super-family have been iden-
tified, and 57 cytochrome P450 enzymes are recog-
nized in humans (237). CYP3A4 is the isoenzyme most
frequently involved in drug metabolism, and accounts
Pain Physician 2008: Opioids Special Issue: 11:S5-S62
S26 www.painphysicianjournal.com
for approximately 50% of marketed drug metabolism,
and levels of CYP3A4 may vary as much as 30-fold be-
tween individuals (238), leading to large variability in
blood levels. The metabolism of more than 90% of the
most clinically important medications can be account-
ed for by 7 CYP isozymes (3A4, 3A5, 1A2, 2C9, 2C19,
2D6, and 2E1) (239). CYP1A2, CYP2C8, and CYP2C9
make up about 10% of the enzymes, CYP2D6 and
CYP2E1 each around 5%, and CYP2C19 around 1%.
CYP2D6 is entirely absent in some populations; for ex-
ample, 6–10% of Caucasians are 2D6 deficient (240),
while other persons have high levels of this enzyme,
leading to rapid metabolism of the medicines.
Table 9. Illustration of activity of opioid receptors.
Mu (µ)
Delta () Kappa (κ)
• Mu 1 – Analgesia
• Mu 2 – Sedation, vomiting,
respiratory depression, pruritus,
euphoria, anorexia, urinary retention,
physical dependence
• Analgesia, spinal analgesia • Analgesia, sedation, dyspnea,
psychomimetic effects, miosis,
respiratory depression, euphoria,
dysphoria, dyspnea
Endogenous Peptides
Enkephalins Agonist Agonist
β-Endorphin Agonist Agonist
Dynorphin A Agonist Agonist
Agonists
Morphine Agonist Weak agonist
Codeine Weak agonist Weak agonist
Fentanyl, sufentanil, Agonist
Meperidine Agonist Agonist
Methadone Agonist
Agonist-antagonists
Nalorphine Antagonist Agonist
Antagonists
Naloxone Antagonist Weak Antagonist Antagonist
Naltrexone Antagonist Weak Antagonist Antagonist
Table 10. DEA schedules of controlled drugs.
Schedule Criteria Examples
I No medical use; high addiction potential Heroin, marijuana, PCP
II Medical use; high addiction potential Morphine, oxycodone, methadone, fentanyl, amphetamines
III Medical use; moderate addiction potential Hydrocodone, codeine, anabolic steroids
IV Medical use; low abuse potential Benzodiazepines, meprobamate, butorphanol, pentazocine, propoxyphene
V Medical use; low abuse potential Buprenex, phenergan with codeine
4.2 Adverse Effects
Complications due to opioid administration concern
all medical practitioners (7,8). Commonly known side ef-
fects of opioids include constipation, pruritus, respiratory
depression, nausea, vomiting, delayed gastric emptying,
sexual dysfunction, muscle rigidity and myoclonus (may
be present in 3 to 87% of cancer patients, may be me-
diated by glycine inhibition in the dorsal horn neurons,
and may be treated by opioid reduction or rotation, as
well as benzodiazepines and baclofen) (241,242), sleep
disturbance (243) (morphine has been shown to reduce
REM sleep via inhibition of acetylcholine release in the
reticular activating formation (244), pyrexia, diminished
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ASIPP Opioid Guidelines
4.3 Drug Interactions
A drug interaction occurs when the amount or
the action of a drug is altered by the administration
of another drug or multiple drugs. Multiple hepatic
drug interactions may influence opioid drug levels
(8,231,232) as illustrated in Table 11.
4.4 Drug Conversions
While there have been multiple opioid conversion
charts developed, none are reliable and none take into
consideration the vast individual differences in effect
and metabolism between patients and within medi-
cations. Brand name and generic medications may
have significant differences in bioavailability, and me-
tabolism of medications may be influenced by genetic
polymorphism and dug interactions. It is therefore im-
portant to recognize that “equipotent” doses of med-
ications may have very different degrees of analgesia
and side effects. In general, to switch between medi-
cations, the clinician must calculate a rough equiva-
psychomotor performance (which appears to be more
of a problem with acute rather than chronic use) (245),
cognitive impairment (246), dizziness and sedation, all
reflecting the effects of opioids at multiple organ sys-
tems (247). Psychostimulants may improve psychomotor
performance scores and subjective drowsiness (248). An
imbalance in the cholinergic/dopaminergic CNS system
is felt to be the mechanism of opioid-induced delirium
(244). Hyperalgesia is a gradual increase in neural re-
sponse to repeated stimulation (249).
Adverse events, in general, appear to fall into 2
broad categories: non-life threatening and life threat-
ening. Hydrocodone may cause sensorineural hearing
loss due to possible genetic polymorphisms. More seri-
ous adverse events such as respiratory depression and
death have been seen with the use of fentanyl buccal
tablets for breakthrough pain. Drug deaths from opi-
oids are a serious and increasing issue. Strong patient
compliance with medical treatment programs is need-
ed to prevent rare but life-threatening adverse events.
Tricyclic antidepressants
Inhibit morphine glucuronidation leading to blood levels
--- Nortriptyline inhibits noncompetitively
--- Amitriptyline and clomipramine inhibit competitively
Methadone and morphine
metabolism of TCAs, leading to toxicity
Quinine
conversion of codeine to morphine leading to ⇓ analgesia
Metoclopramide Earlier peak plasma levels with controlled-released opioids
Meperidine MAO inhibitors trigger hyperpyrexia
Propoxyphene
carbamazepine, doxepin, metoprolol, propranolol levels
excretion of benzodiazepines, leading to accumulation and overdose
Erythromycin
opioid effects
Venlafaxine
methadone levels
Rifampin
Phenytoin
Carbamazepine
methadone levels
Phenytoin
Phenobarbital
meperidine levels
CY2D6 inhibitors
tramadol levels
analgesia from hydrocodone/codeine
CY2D6 substrates
tramadol levels because of competition for metabolism
CYP3A4 inhibitors
methadone levels
CYP3A4 inducers
methadone levels
Methadone and morphine
metabolism of desipramine, leading to toxicity
Table 11. Drug interactions of opioids.
Pain Physician 2008: Opioids Special Issue: 11:S5-S62
S28 www.painphysicianjournal.com
lent 24-hour dose, divide by the dosing schedule, and
then “under-dose,” especially with methadone, with
subsequent titration to effect.
4.5 Opioid Therapy and Side Effects
Multiple reviews (231-235,250) described opioid
pharmacology of agonists, antagonists, partial ago-
nists, agonists and antagonists, peripherally-acting
opioids, combination opioid analgesics, and variations
in opioid responsiveness. Implications and side effects
of long-term opioid therapy include opioid-induced
immunologic effects, hormonal changes, hyperalge-
sia, sedation, sleep disturbances, psychomotor distur-
bances, constipation, bladder dysfunction, and cardiac
effects (8). Opioid complications and side effects in de-
tail along with appropriate management of these side
effects were described (8).
5.0 termInology of abuse and
a
ddIctIon
5.1 Introduction
The terminology related to abuse and addiction
of opioids and other controlled substances is consid-
ered confusing and reflects lack of understanding of
multiple issues related to abuse and addiction. There
are 3 fundamental concepts related to addiction:
1) the determination of addiction rests with the user
even though some drugs produce pleasurable
reward:
2) addiction is a multidimensional disease with neuro-
biological and psychosocial dimensions: and
3) addiction is a phenomenon distinct from physical
dependence and tolerance.
Addiction is related to the “reward center” lo-
cated within the mesocorticolimbic dopamine systems
in the brain (251). Up-regulation of cAMP pathways
in the brain (locus coeruleus) and spinal cord leads to
acute physical withdrawal symptoms when the ad-
ministered opioid is reduced or stopped, resulting in
excessive central norepinephrine release, and its mani-
festations (252). Addiction is therefore a physiologic
response, influenced by a variety of psychosocial issues
(such as depression and anxiety) as well as genetic is-
sues (family history of addiction).
5.2 History
More than a century ago, the debate over how
best to address the misuse and abuse of prescription
medications began, at a time when the most com-
monly abused drugs were freely available (253). As an
example, heroin (diacetyl morphine) was developed
to help morphine addicts; “heroin was sold over the
counter as a soothing syrup for colicky babies and co-
caine was the reason a then-new beverage invented in
an Atlanta pharmacy was called ‘Coke’ (254).”
5.3 Terminology
Despite significant growth in understanding of
the scientific basis of addiction, definitions and diag-
nostic criteria based on obsolete conceptualization of
addiction persist. The following terms have been de-
fined by World Health Organization (WHO), DSM-IV,
and United States Federal and State policies, and oth-
er organizations by means of consensus statements.
There continues to be confusion and misunder-
standing concerning the term “addiction.” The Con-
trolled Substance Act defined addiction as a term
meaning any individual who habitually uses any nar-
cotic drug so as to endanger the public morals, health,
safety, or welfare or who is so far addicted to the use
of narcotic drugs as to have lost the power of self-con-
trol with reference to his or her addiction (255).
5.3.1 Substance Abuse
DSM-IV defines substance abuse as a maladaptive
pattern of substance use leading to significant impair-
ment or distress in the last 12 months with one (or
more) events such as failure to fulfill major role obli-
gations, using inappropriate substances, participating
in hazardous situations, being involved in recurrent
substance related legal problems, and/or continuing
use in the face of adverse consequences.
5.3.2 Substance Dependence
DSM-IV defines substance dependence as a mal-
adaptive pattern of substance use leading to sig-
nificant impairment or distress in the last 12 months
meeting the criteria for substance abuse plus 3 or
more of the following 7 criteria during the same
12-month period: tolerance, withdrawal, inability
to control use, unsuccessful attempts to decrease or
discontinue use, a great deal of time lost in obtain-
ing the substance, using the substance, or recover-
ing from its effects, important activities are given
up because of use, continued use despite physical or
psychological problems caused by use, and continued
use of a substance.
5.3.3 Tolerance
The need for an increased dosage of a drug to
produce the same level of analgesia that previously
existed is defined as tolerance. Tolerance also suspect-
www.painphysicianjournal.com S29
ASIPP Opioid Guidelines
Psychosocial
Psychological
(Genetic factors)
Depression
Anxiety
Somatoform disorder
Personality disorder
Atypical stress responsivity
Social and Environmental
Circumstances of drug use
Poverty
Childhood abuse
Unemployment
Peer pressure
Drug
Initiation
Sti
mulates mesocorticolimbic reward circuitry
Mode of administration/formulation enhances
euphoria (eg IV, snorted)
Maintenance
Produces tolerance and dependence (negative
reinforcement)
Produces enduring neuroadapatations
associated with lifelong craving
Withdrawal and Abstinence
Anhedonic state
Negative reinforcement
Genetic
Vulnerability
Family history of addiction
Personality disorder
Gene variants associated with risk taking
and impulsivity (initiation phase)
Atypical stress responsivity
Drug Disposition
Pharmacokinetic genes affecting drug
metabolism and transport
Pharmacodynamic genes affecting pain
and analgesic responses, dependence
and addiction
Fig. 5. Contributions to addiction.
Adapted from Ballantyne (6). Opioid analgesia: Perspectives on right use and utility. Pain Physician 2007; 10:479-491.
ed when a reduced physiologic effect is observed with
constant dosing. Analgesic tolerance is not always
evident during opioid treatment, and is not to be con-
fused with addiction, which occurs as a dysfunctional
craving of a drug action by physiologic action and psy-
chologically driven factors.
5.3.4 Withdrawal
Withdrawal describes a characteristic set of symp-
toms that occur when a substance is withdrawn, and
those symptoms disappear when the substance is
reintroduced.
5.3.5 Physical Dependence
Physical dependence is a state of adaptation
that is manifested by a drug class specific withdrawal
syndrome that can be produced by a drug cessation,
rapid dose reduction, decreasing blood level of the
Pain Physician 2008: Opioids Special Issue: 11:S5-S62
S30 www.painphysicianjournal.com
drug, and/or administration of an antagonist. Physi-
cal dependence is a normal adaptation to the drug,
reinforced by continued use. Physical dependence is
most commonly associated with withdrawal symptoms
when the substance is abruptly discontinued, and is
seen in many classes of medication not associated with
addiction, such as beta blockers.
5.3.6 Addiction
In contrast to tolerance, withdrawal, and physi-
cal dependence, addiction is compulsive use of a drug
despite physical harm, and the terms tolerance and
addiction are not interchangeable. The terminology
may share similar characteristics, as many addicts do
become tolerant of their chosen drug, which can be
expected with regular use. Addiction i