Transcript Opioids and Chronic Benign Pain: A Different Perspective

Opioids and Chronic Benign Pain:
A Different Perspective
William O. Witt, M.D.
Chairman Emeritus, Anesthesiology
Director, Interventional Pain Associates / UK Healthcare
Professor, Anesthesiology, Neurosurgery and Hematology-Oncology
University of Kentucky Medical Center
Lexington, Kentucky
“It is more important to know
what kind of patient has a
disease…
than what kind of disease
a patient has”
-Sir William Osler
There are many ways to treat pain,
but they fall into two broad categories…
• Palliation - Do whatever is necessary to reduce
pain within the constraints of function
• Rehabilitation - Do whatever is necessary to
increase function within the constraints of pain
• Either is acceptable practice, but…
• They are mutually exclusive!
Compare and Contrast
Palliative
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Pain - do something
Measure the pain
Don’t measure the function
Conditioned responses are
expected - “breakthrough
medication”
• Pain behavior is expected
and rewarded - phone in a
prescription
• Orally administered opioids
may be effective
• Behavioral Medicine is
optional
Rehabilitative
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Pain - do something else
Measure the function
Don’t measure the pain
Conditioned responses are to
be avoided - only scheduled
medication
• Pain behavior is ignored and
ultimately extinguished
(phone calls: three responses)
• Self-administered opioids are
usually ineffective
• Behavioral Medicine is
essential
Opioid Sales are Inconsistent
with Expected Indications
• No other category of drug has matched this rate of
growth for such an ill-defined “diagnosis” as CNMP
• Oxycodone sales increased 383% between 1997 and 2002
• Methadone sales increased 392% between 1997 and 2002
-Paulozzi & Ryan, Am. J. Prev. Med., 2006
• More than 80% of patients who use trans-mucosal fentanyl do
not have cancer, its only FDA-approved indication
-ImpactRx 2005-2006 survey data
• Diversion of controlled substances is now the most
common source for illicit distribution
- SAMHSA, National Survey on Drug Use & Health, 2004
Published Standards for
Prescribing Opioids for CNMP
Jovey, et.al., Pain Res. Mgmt., 2002
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Detailed history, examination and laboratory studies
Complete and consistent diagnosis
Should be “one of the last (sic) therapeutic options”
No history of substance abuse, including ETOH
Informed consent
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Pros and Cons of opioid therapy
Defined goals of treatment
Opioid contract
Explicit assumption of risk for driving
Published Standards for
Prescribing Opioids for CNMP
Jovey, et.al., Pain Res. Mgmt., 2002
• Defined trial prior to long-term treatment with
documentation of:
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Decreased pain
Improved function
Absence of adverse effects
Appropriate urine drug screens during trial
Setting of upper dose limit for trial
Absence of abnormal behaviors
Published Standards for
Prescribing Opioids for CNMP
Jovey, et.al., Pain Res. Mgmt., 2002
• Absence of “Abnormal Behaviors”
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Lost, stolen, or forged prescriptions
Concurrent illicit drug use
Unauthorized escalation of dosage or frequency
Visits without appointments
Frequent office phone calls
Diversion, known or unknown
Usage of other peoples’ prescriptions
Multiple prescribers
Phone calls after hours
Physical signs of abuse
Failure to keep appointments
Published Standards for
Prescribing Opioids for CNMP
Jovey, et.al., Pain Res. Mgmt., 2002
• If abnormal behaviors are identified
• Trial should be declared a failure
• Opioids should be reduced gradually and stopped
Risk to Society
• “The diversion of prescription opioids
has become a major public health hazard”
-Paulozzi, et.al., 2006
• Between 1990 and 2002, deaths due to
prescription opioid analgesic overdose have
increased 91.2%
• In the same period, deaths from heroin and
cocaine have increased 12% and 22.8%
respectively
Risk to Society
• In 2002 alone, there were 4451 deaths from
prescription opioids, more than heroin and
cocaine combined
• 1061 from heroin
• 2569 from cocaine
• Although hydrocodone and oxycodone
preparations are prescribed 10 times more
frequently, methadone accounts for more
deaths than both of these preparations
combined
Risk to Society
• Most of the diverted medication finds its way
into the community via fraudulent
prescriptions, theft, or failure to dispose of
unused medication
• “Actiq has been associated with 127 deaths.
Two of them involved children who confused
the drug for (sic) candy.”
-Cephalon data as reported in The Wall Street Journal
Long-term Safety Has Not
Been Demonstrated
• Despite the apparent absence of direct organspecific toxicity, opioids nonetheless produce
many adverse effects
• Hyperalgesia
-Mao, Pain, 2002
• Respiratory depression associated with chronic use of
opioids alone or due to drug interactions has simply not
been studied
-Farney, et.al., Chest, 2003
• Although risk of addiction is very low in the acute use of
prescription opioids, the risk in long-term use is probably
about 10% and may be as high as 16% in the general
population
-Savage, JPSM, 1996
Long-term Safety Has Not
Been Demonstrated
• Hormonal Imbalance
-Ballantyne & Mao, NEJM, 2003
-The Pain Society, 2004
-Daniell, J. Pain, 2002
• Sleep disorders
• Adrenal suppression
• Decreased testosterone in males
• Erectile dysfunction
• Depression
• Secondary risk of hormone replacement
Long-term Safety Has Not
Been Demonstrated
• Hormonal Imbalance
-Ballantyne & Mao, NEJM, 2003
-The Pain Society, 2004
-Daniell, J. Pain, 2002
• Sleep disorders
• Adrenal suppression
• Decreased estradiol in females
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Infertility
Osteoporosis
Depression
Secondary risk of hormone replacement
Long-term Safety Has Not
Been Demonstrated
• Myoclonus
• Immune suppression
-Ballantyne & Mao, NEJM, 2003
-Roy, et.al., J.Neuroimmune Pharm., 2006
• “…there is general agreement that chronic
morphine treatment compromises host defense…”
• “It is clear that both acute and chronic morphine
treatment affect innate and adaptive immunity.
These effects will have immense therapeutic
consequences.”
Long-term Safety Has Not
Been Demonstrated
• There is legal risk as well
• It is a criminal offense in all states to drive a
vehicle while under the influence of drugs
• The drugs themselves need not be illegal, but
can be prescription or even over-the-counter
• Only 36% of opioid contracts surveyed referred
to this assumption of risk
Fishman, et.al., JPSM, 1999
Long-term Safety Has Not
Been Demonstrated
“The laws do not differentiate
between acute use and long-term use
of opioids, and patients need to be
made aware of this aspect of their
treatment”
-Antoin and Beasley, Postgraduate Medicine, 2004
Long-term Efficacy Has Not
Been Demonstrated
• We have failed to require the same rigor for this
practice that we require for other medical therapies
• The significance of Dr. Portenoy’s 1986 article is
profound, yet it is still a retrospective case series of
38 patients
• Since this article, there have been numerous
editorials, case reports and a few open-label studies of
treatment over a period of several weeks
Long-term Efficacy Has Not
Been Demonstrated
• There has not been a prospective study demonstrating
long-term functional improvement
• There has not been a prospective study demonstrating
long-term analgesia
• In contrast, there is a significant and increasing body
of literature demonstrating long-term hyperalgesia
• This literature does not necessarily apply to the
intrathecal delivery of opioids
In 1983 Dr. Martin demonstrated
in a canine model:
• The existence of an endogenous kappa opioid
peptide in the pontine-medullary region of the
brainstem…
• That the administration of low doses of naloxone
to this region produced analgesia…
• That whereas low doses produced analgesia,
higher doses produced hyperalgesia…
• That this center may be activated by the exposure
of higher brain centers to exogenous opioids
“It may be that the opioid peptides play
a dual role in modulating the perception
of pain and not only obtund this
sensation but [also] facilitate its
recognition and that the balance of these
two processes may differ among
indivuduals and according to pathologic
as well as physiologic states”
William R. Martin, M.D., Ph.D.
Department of Pharmacology
University of Kentucky College of Medicine
Life Sciences, 1983
Whereas Gillman and Lichtigfeld
had previously proposed the
existence of opposing systems,
Dr. Martin was the first to
demonstrate that this system was
opioid-based
What do we know about opioidinduced hyperalgesia?
• Not everything, and a lot more than nothing
• It occurs more frequently in the young
• It is probably on the same receptor that produces
euphoria
• It is probably on the same receptor that produces
the abstinence syndrome
• It occurs with the first dose of an opioid and is
exacerbated by each subsequent dose
• If the pain condition is stable and the pain is
worse, the opioids are not the solution, they are
the problem
Hyperalgesia
• “…apparent opioid tolerance is not synonymous
with pharmacological tolerance, which calls for
opioid dose escalation, but may be the first sign of
opioid-induced pain sensitivity suggesting a need
for opioid dose reduction….”
• “…repeated opioid administration could lead to a
progressive and lasting reduction of baseline
nociceptive thresholds, hence an increase in pain
sensitivity….”
• Mao, Pain, 100 (2002) 213-217