Presentation was originally done at Group Health Cooperative’s National Summit on Opioid Safety: http://www.ghinnovates.org/?p=3502 Presentation by: Roger Chou, MD, Associate Professor of Medicine for Oregon Health & Science University and Director of Pacific Northwest Evidence-based Practice Center.

1. State of the evidence on chronic
opioid therapy and risk mitigation
Roger Chou, MD
Associate Professor of Medicine
Oregon Health & Science University
D i r e c t o r, P a c i f i c N o r t h w e s t E v i d e n c e - b a s e d P r a c t i c e C e n t e r

2. Conflict of interest
disclosure
Dr. Chou has received research funding from the Agency for
Healthcare Research and Quality, the Drug Effectiveness Review
Project, and the American Pain Society; and has received
honoraria from the American Pain Foundation.
Dr. Chou has financial relationships with Wellpoint Inc., Blue
Cross Blue Shield Association, and Palladian Health for
implementation of low back pain guidelines.
There will be no unannounced disclosures of off-label use of
drugs, biologics or medical devices

3. Purpose
• Understand what we know and don’t
know about long-term opioid therapy
• Discuss clinical and policy implications

4. Background
• Chronic noncancer pain is highly prevalent, with
substantial burdens
• Estimates vary, up to 1/3 of adults report some CNCP
• Opioids are increasingly prescribed for chronic
noncancer pain
• About 5% of adults report use of LOTa
• Opioids are associated with potential harms, both
to patients and to society
• Large practice variations in use of LOT
aBoudreau et al Pharmacoepidemiol Drug Saf 2009

6. Nonmedical Use of Prescription Pain Relievers in the Past Month,
by Age Group: Percentages, 2002 to 2007

7. 7
Street value of opioids
Drug Estimated street value
Oxycontin $3-4/mg (40 mg tab=$120-$160)
Oxycodone/APAP $15/tab
Hydrocodone/APAP $6-12/tab
Codeine/APAP $2-4/tab
Propoxyphene/APAP $2-20/tab
Hydromorphone $15/tab
Morphine $1/mg
Methadone $1-2/mg

8. 8
Guidelines and the state of evidence on LOT
• Two recent guidelines addressed multiple areas
related to LOT, including risk assessment, patient
selection, opioid initiation, monitoring, and risk
mitigation
• American Pain Society/American Academy of Pain
Medicine (2009)
• 21 of 25 recommendations (84%) viewed as supported by only low-
quality evidence
• Canadian Guideline (2010)
• Only 3 of 24 recommendations classified as based on RCTs
• 19 recommendations based solely or partially on consensus
opinion

9. 9
Randomized Trial Evidence for Commonly
Used Medications from Recent Meta-Analyses
Medication class Number Number Person- Number US
of trials of patients years adults using long-
(est.) term
Antihypertensivesa 147 ~464,000 ~1,857,000 48 million
Statinsb 26 ~169,000 ~753,000 34 million
NSAIDsc 31 ~116,000 ~117,000 6 million
Opioidsd 62 ~12,000 ~1,500 7-9 million
a. Law et al., BMJ 2009.
b. CTT Collaboration, Lancet 2010.
c. Trelle et al., BMJ 2011.
Courtesy Michael Von
d. Furlan et al. Pain Res Manage 2011.
Korff

10. Evidence on • Short-term efficacy
effectiveness • 62 RCT’s in one recent meta-analysis, duration
<16 weeks in 61a
of LOT for
• Opioids more effective than placebo for
chronic non- nociceptive and neuropathic pain (effect sizes
cancer pain 0.55-0.60)
• Long-term effectiveness
• Cochrane review included 26 studies >6 monthsb
• 25 studies were case series or uncontrolled long-
term trial continuations
• Many discontinuations due to adverse effects
(23%) or insufficient pain relief (10%), but some
evidence that patients who continue on opioids
experience long-term pain relief
aFurlan et al. Pain Res Manag 2011
bNoble et al. Cochrane Database Syst Rev 2010

11. Other
limitations of • In general, effects on function are
the evidence smaller than effects on pain, with
some trials showing no or minimal
on
benefit
effectiveness
of LOT
• Trials typically excluded patients at
higher risk for abuse or misuse,
psychological comorbidities, and
serious medical comorbidities
• Limited evidence on commonly
treated conditions
• Low back pain, fibromyalgia, headache,
others
• No trials compared LOT vs. CBT-
based exercise therapy or
interdisciplinary rehabilitation

12. • Trials generally found no difference
between opioids in efficacy, based on
Comparative short-term trials
effectiveness • No clear difference in efficacy between
of opioids for long- and short-acting opioids, but trials
CNCP designed to evaluate equivalence using
efficacy designsa
 Practice of long-acting, round-the-clock dosing
based on cancer guidelines and expert opinion,
potential benefits not proven
 Long-acting, round-the-clock opioids may
induce tolerance and result in higher doses
• Limited evidence on the efficacy of a
number of specific opioids
• Methadone evaluated in a single, small, poor-
quality trial of neuropathic painb
aCarson et al. http://www.ncbi.nlm.nih.gov/books/NBK62335/pdf/TOC.pdf 2011
bMorley et al. Palliative Med 2003

13. 13
FDA Public Health Advisory, November
2006
“Methadone Use for Pain Control May
Result in Death and Life-Threatening
Changes in Breathing and Heart
Beat”
What prompted this warning?
http://www.fda.gov/Drugs/DrugSafety/PublicHealthAdvisories/ucm1243

14. • Increased methadone deaths nationwide
Methadone • Half-life 15 to 60 hours, up to 120 hours
 60 hour half-life=12 days to steady-state
 Prolongation of QT intervals, sudden death
 Start at 2.5 mg q8 hrs, increase slowly
• Little evidence on use of methadone for
CNCP
 One small, poorly designed trial
 A VA cohort study found methadone
associated with lower mortality risk compared
to morphinea
 No evidence on effects of alternative dose
titration strategies
 No evidence on effects of ECG monitoring on
risks associated with methadone
aKrebs EE et al. Pain 2011;152:1789-1795

16. • High rates of adverse events
• Constipation, nausea, sedation, and others
• Hyperalgesia
• Paradoxical increased sensitivity to pain
Harms of • Prevalence, risk factors and clinical significance
not well understood
opioids • Hypogonadism
• Primarily based on cross-sectional studies
• Clinical significance not well understood
• Falls/fracture risk
• Some studies show increased risk of
poor functional outcomes
• One study of patients in WA state workers’
compensation system with low back injury
found increased risk of disability at 1 year in
patients who received opioids within 6 weeks
(adjusted OR 2.2, 95% 1.5 to 3.1)
aFranklin et al. Spine 2008

17. • Estimates vary from 4% to 26%, or
higher
Abuse,
• One study (n=801) based on
standardized interviewsa
addiction, • 26% purposeful oversedation
misuse • 39% increased dose without prescription
• 8% obtained extra opioids from other
doctors
•
18% used for purposes other than pain
•
12% hoarded pain medications
• Definitions inconsistent across
studies and behaviors evaluated vary
in seriousness
• Poorly standardized methods to
detect these outcomes
• Data from efficacy trials
aFleming et al. J Pain 2007
underestimate risks

18. • Strongest risk factor for opioid abuse
is personal or family history of
Risk substance abusea
assessment • Other risk factors in some studies:
depression, younger
age, preadolesecent sexual abuse in
women
• Risk assessment instruments are
available, but none has been well-
validated
• No evidence on effects of using risk
assessment instruments to guide patient
selection on clinical outcomes
aChou et al. J Pain 2009

19. 19
Risk prediction tools
Number of items
and cut-off Sensitivit Specificit
Instrument score y y PLR NLR
SOAPP 14 (max 67), ≥7 0.91 0.69 2.90 0.13
Version 1*
SOAPP-R* 24 (max 96), ≥17 0.80 0.68 2.50 0.29
ORT 10 (max 25), NA NA Low risk: NA
0-3 (low risk), 0.08
4-7 (mod risk), Mod risk:
>7 (high risk) 0.57
*Derivation study High risk:
14.3

20. 20
Risk prediction tools: application
Post-test Post-test
Pre-test probability with probability with
Instrument probability positive screen negative screen
SOAPP V1 or 3% 7-8% <1%
SOAPP-R
SOAPP V1 or 20% 40% 3-7%
SOAPP-R
ORT 3% High risk: 30% Low risk: 0.2%

21. • Informed consent generally required in
Risk mitigation all patients
strategies • Long-term opioid therapy management
plan recommended by APS/AAPM and
Canadian guidelines
• No data showing that management plans
reduce risk of overdose, abuse or misuse, or
on optimal components of management plan
• No evidence on optimal monitoring
intervals or utility of pill counts

22.  Available now in many states
Prescription
 Studies show that use of PDMPs can
drug
identify cases of diversion and doctor
monitoring
shopping
programs
 Recent study found decreased inappropriate
drug prescribing with use of a centralized
prescribing system in Canadaa
 Effects on clinical outcomes (e.g., overdose)
not known
 Use variable and generally suboptimal
 PDMPs vary in who can access,
information not available across states
aDormuth et al. CMAJ 2012

24. Urine drug  Diagnostic accuracy for presence or
tests absence of a drug at a defined
concentration in the urine is well-
established
 Some false-positives or -negatives can occur
based on dose, differences in rates of
metabolism, cross-reaction, uncommon
metabolites
 Diagnostic accuracy for
abuse/addiction not well studied
 No evidence on effects of UDTs on
clinical outcomes
 No evidence comparing individualized
(e.g., based on assessed risk) vs. more
standardized testing
 Chou et effectiveness not well studied
Cost al. J Pain 2009

25.  Several instruments available,
including the COMM (related to the
Monitoring SOAPP) and the PADT (mainly a
instruments documentation instrument)
 Instruments not well validated
 No evidence on effects of using
different monitoring instruments (or
different methods of monitoring) on
patient outcomes

26. Opioid-  Opioid-deterrant formulations have
deterrant recently been approved by FDA or
formulations undergoing FDA approval process
 Designed to be tamper-resistant or co-
formulated with medications that reverse
opioid effects or produce noxious side effects
when tampered with
 Effectiveness for reducing misuse/substance
abuse and improving clinical outcomes yet to
be established
 Likely to be primarily effective in patients who
crush or inject opioids
 One study found patients placed on a new
tamper-resistant formulation of long-acting
oxycodone frequently switched to an
alternative opioid or heroina
aCicero et al. NEJM 2012

28. 28 Purdue Settles Oxycontin Charge For
$600M
"Purdue ... acknowledged that it illegally marketed and
promoted OxyContin by falsely claiming that
OxyContin was less addictive, less subject to abuse
and diversion, and less likely to cause withdrawal
symptoms than other pain medications - all in an
effort to maximize its profits“
-U.S. Attorney John Brownlee, May
2007
http://money.cnn.com/2007/05/10/news/companies/oxycontin/index.htm?cnn=yes

29. Dose • No theoretical ceiling with opioids
escalations  But, little evidence to guide prescribing at
higher doses
 Additional risks
(hyperalgesia, endocrine), unclear
benefit, and can be a marker for
abuse, addiction, or diversion
 Higher doses may be associated with
higher risk
• APS/AAPM and Canadian panels
defined >200 mg/day of morphine (or
equivalent) as “higher dose”
 Based on doses evaluated in trials and
observed in cohorts
 Other guidelines use lower threshold for
high dose
 Need trials comparing dose escalations
beyond certain thresholds and alternative
management strategies

30. • 3 large observational studies on opioid dose
and risk of overdose or death
 Cohort study (n=9940, 51 opioid overdoses, 6
fatal)
 Risk of opioid overdose (vs. 1to <20 mg/day)
Dose-response  >=100 mg/d: HR 8.9 (4.0-20)
 50 -<100 mg/d: HR 3.7 (1.5-9.5)
relationship for  20-<50 mg/d: HR 1.4 (0.57-3.6)
opioids and  Case-control study (VA, 750 cases)
 Risk of opioid overdose-related death (vs. 1 to
overdose <20 mg/day)
 >=100 mg/d: HR 7.2 (4.8-11)
 50-<100 mg/d: HR 4.6 (3.2-6.7)
 20-<50 mg/d: HR 1.9 (1.3-2.7)
 Nested case-control study (Ontario, 498 cases)
 Risk of opioid-related mortality (vs. 1 to <20
mg/day)
 >=200 mg/d: OR 2.9 (1.8-4.6)
 100-199 mg/d: OR 2.0 (1.3-3.2)
 50-99 mg/d: OR 1.9 (1.3-2.8)
 20-49 mg/d: OR 1.3 (0.94-1.8)
Dunn et al. Ann Intern Med 2010;152:85-92; Bohnert et al. JAMA
2011;305:1315-21; Gomes et al. Arch Intern Med 2011;171:686-
91

31. Effects of dose • In 2007, WA state implemented dosing policy of <120
mg/day morphine equivalents in workers’
compensationa
limitation • After 2007, proportion prescribed >120 mg/day
decreased by 35%
strategies and • 50% decrease from 2009 to 2010 in number of opioid-
related deaths
policies on • Data observational, subject to confounding and attribution
bias, overdose trend based on a single year
opioid-related • One RCT found no difference in usual pain or
functional disability between a stable dose prescribing
deaths strategy vs. a more liberal dose escalation strategy,
but doses were relatively low (52 vs. 40 morphine
equivalents/day)b
• No difference in rates of opioid misuse; 27% discharged
due to opioid misuse or noncompliance
• Not designed to assess mortality
aFranklin et al, Am J Industrial Med 2011
bNaliboff et al. J Pain 2012

32.  Few studies evaluated optimal
Discontinuatio methods for discontinuing opioids in
n of opioid patients prescribed LOT for chronic
pain
therapy
 Long-term follow-up of patients who
discontinue LOT is lacking

33. • Opioids may cause somnolence,
Driving and incoordination, clouded mentation, or
work safety slower reflexes
• Impairment probably more likely when
starting therapy, when increasing
doses, and when using other drugs
with psychoactive effects, but data are
sparse
• No evidence that patients on stable
doses of opioids at higher risk for
MVA, but studies likely impacted by
self-selection bias

34. Risk • REMS plan approved by FDA
evaluation and July 2012
mitigation • Primarily for schedule II, long-acting or
strategies extended release opioids
• Voluntary prescriber continuing
education (not required for DEA
licensure); financial support by
manufacturers mandatory
• Patient education document for
prescribers to go over with the patient
• Medication Guide (MedGuide) for
pharmacists to dispense with the
medication
• Knowledge assessment and
independent third-party audits of
continuing education content
• Expected to be available March 2013

35. • Data on long-term benefits sparse and
opioids may have little effect on (or
worsen) functional outcomes
Clinical • Sparse evidence on patients at higher risk
implications for abuse and for a number of commonly
encountered conditions
• Clear dose-dependent risks of
opioids, starting at relatively low
doses, with limited evidence on benefits of
higher doses
• No opioid is “safe”
• Taken together, the available evidence
suggests that potential benefits of opioids
are at best finely balanced with harms
• More selective and cautious prescribing
appears indicated
• Need to assess risk as standard practice
• Routine integration of risk mitigation strategies
matched with level of assessed risk

36. • Efforts to address opioid prescribing
Implications practices must be multifactorial and
address barriers to effective treatment of
for health chronic pain
plans • Lower opioid dose parameters
• Efforts to lower doses may be most efficiently
directed initially towards patients not already on
high doses
• Exceptions based on documented functional
improvement and risk assessment?
• Provide readily accessible alternatives to
opioids
• Exercise therapy and cognitive behavioral
therapy
• Interdisciplinary rehabilitation for complex
patients
• Encourage coordinated approaches to pain
management
• Care management teams and access to
additional expertise
• Training in cognitive behavioral principles
• Identify high-risk opioid prescribing using
EMRs and other resources
• Based on dose, co-prescribed medications,