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Summary
Optimal
pharmacologic management of pain requires selection of the appropriate analgesic
drug, prescription of the appropriate dose, administration of the analgesic by
the appropriate route, scheduling of the appropriate dosing interval, prevention
of persistent pain and relief of breakthrough pain, aggressive titration of the
dose of the analgesic, prevention, anticipation, and management of analgesic
side effects, utilization of appropriate coanalgesic drugs, and consideration of
sequential trials of opioid analgesics. . OxyContin has the characteristics of
an “ideal” opioid analgesic drug: short half-life, long duration of action,
predictable pharmacokinetics, absence of clinically active metabolites, rapid
onset of action, easy titration, no ceiling dose, minimal adverse effects, and
minimal associated stigma. OxyContin has been shown to be effective in the
control of pain caused by cancer, osteoarthritis, post-herpetic neuralgia, major
surgery, and degenerative spine disease. Efforts
to reduce public abuse of OxyContin must not interfere with ready access of this
essential medicine by legitimate patients.
Pharmacologic
Management of Chronic Pain
There
are four basic approaches to pain control: modify the source of pain, alter
central perception of pain, modulate transmission of pain to the central nervous
system, and block transmission of pain to the central nervous system (Jacox et
al 1994, Levy 1996, Doyle et al 1997, American Pain Society 1999).
Systemic pharmacologic management aimed at the first three of these
approaches is the cornerstone of the treatment of most patients with moderate to
severe pain (Jacox et al 1994, Levy 1996).
Optimal pharmacologic management of pain requires selection of the
appropriate analgesic drug, prescription of the appropriate dose, administration
of the analgesic by the appropriate route, scheduling of the appropriate dosing
interval, prevention of persistent pain and relief of breakthrough pain,
aggressive titration of the dose of the analgesic, prevention, anticipation, and
management of analgesic side effects, utilization of appropriate coanalgesic
drugs, and consideration of sequential trials of opioid analgesics (Table 1.)
(Levy 1996).
The
World Health Organization created a Three-Step Analgesic Ladder in 1990 (World
Health Organization 1990). Step 1,
non-opioid analgesics such as acetaminophen and non-steroidal anti-inflammatory
drugs are limited to the treatment of mild pain due to their low maximal
efficacy and their potential for end-organ toxicity. Step 2 opioid drugs such as
codeine, and hydrocodone, and oxycodone are limited to the control of moderate
pain due to the intrinsic dose-limiting side effects of codeine, their
dose-limiting, fixed combinations with non-opioid, Step 1 analgesics, and their
availability only as immediate-release formulations.
Relief of moderate to severe acute and chronic pain is best achieved with
an opioid analgesic from Step 3 of the WHO Analgesic Ladder: morphine, oxycodone,
hydromorphone, or fentanyl (Jacox et al 1994, Levy 1996, American Pain Society
1999). Morphine has been the most
commonly used Step 3 opioid analgesic for past thirty years. The introduction of
MS Contin (controlled-release morphine), twenty years ago, set the standard for
the control of chronic pain with just twice-a-day, analgesic dosing (Hanks 1989,
Thirwell et al 1989).
OxyContin:
An Ideal Opioid Analgesic
Oxycodone
became extended from Step 2 to Step 3 with the availability of single-entity
immediate-release oxycodone (IRO) tablets and liquids.
Clinical studies and practical experience with these formulations showed
that oxycodone had no apparent dose ceiling, less side effects than other
opioids in individual patients, and less social stigma than morphine (Kalso and
Vaino 1990, Glare and Walsh 1993, Levy 1996). OxyContin has been available in
the USA for five years and has been shown to be effective in the control of pain
caused by cancer (Hagen and Babul 1997, Citron et al 1998), osteoarthritis
(Caldwell et al 1999, Roth et al 2000), post-herpetic neuralgia (Watson and
Babul 1998), major surgery (Sunshine et al 1996), and degenerative spine disease
(Hale et al 2000). OxyContin is
comparable and preferable to IRO and is comparable to MS Contin for the control
of cancer pain (Bruera et al 1998, Kaplan et al 1998, Mucci-LoRusso et al 1998). OxyContin is approximately twice as potent as MS Contin on a
milligram per milligram basis (Bruera et al 1998, Curtis et al 1999).
OxyContin
has the characteristics of an “ideal” opioid analgesic drug: short
half-life, long duration of action, predictable pharmacokinetics, absence of
clinically active metabolites, rapid onset of action, easy titration, no ceiling
dose, minimal adverse effects, and minimal associated stigma (Table 2.).
Oxycodone has a serum half-life of 3-5 hours with steady state reached in
24-36 hours (Kalso and Vaino 1990, Glare and Walsh 1993). Double-blind studies
have shown that OxyContin given every 12 hours is as effective as an equivalent
dose of IRO given every 6 hours (Kaplan et al 1998, Hale et al 2000).
OxyContin has a biphasic absorption with a minor, initial peak at 0.6
hours and a secondary, major peak at 6.2 hours (Kaiko et al 1996b, Mandema et al
1996, Benziger et al 1997). Clinical
analgesia has an onset within 1 hour and a duration of 12 hours (Mandema et al
1996, Sunshine et al 1996). The
bioavailability of oxycodone is 60-87 % which increases the predictability of
its pharmacokinetics (Kalso and Vaino 1990, Kalso et al 1991, Reder et al 1996). Clinically, the predictable pharmacokinetics of OxyContin are
demonstrated by the independence of its dissolution on pH and the high
correlation of its dose with its plasma level (Kaiko et al 1996b, Benziger et al
1996, Kaiko 1997, Mucci-LoRusso et
al 1998, Mandema et al 1998). OxyContin’s bioavailability is increased by 15 %
in the elderly and approximately 50 % in renal dysfunction (Kaiko et al 1996b,
Kaiko 1997, Mucci-LoRusso et al
1998, Mandema et al 1998). OxyContin has less plasma variation than morphine (Colucci
et al 1998) and has no clinically significant active metabolites (Kaiko et al
1996a, Heiskanen et al 1998). The time-action of oxycodone’s drug effect
coincides with its time-concentration. Its
drug effect is not altered by inhibition of oxymorphone formation with quinidine
(Kaiko et al 1996b, Heiskanen et al 1998).
Because of its biphasic absorption, OxyContin has an onset of pain relief
of 46 minutes, which is almost as rapid as the analgesic onset of IRO at 41
minutes (Sunshine et al 1996, Kaiko 1997).
The mean time to peak pain relief for 40 mg of CRC is 1:29 hours compared
to 2:20 hours for MS Contin (Sunshine et al 1996, Kaiko 1997).
Combined data from several controlled studies with OxyContin and MS
Contin showed that OxyContin was easily titratable and had no ceiling dose (Kaiko
et al 1996b, Heiskanen and Kalso 1997, Mucci-LoRusso et al 1998, Bruera et al
1998, Curtis et al 1999). The
average daily dosage of OxyContin in these studies was 120 mg with an
equianalgesic ratio of morphine to oxycodone of 2:1 (Mucci-LoRusso et al 1998,
Bruera et al 1998, Curtis et al 1999). Common
opioid-induced adverse effects were minimal with OxyContin and diminished over
time with the same tolerance observed with other opioids (Bruera et al 1998,
Kaplan et al 1995). Fewer patients
taking OxyContin experienced severe adverse effects and more had no adverse
effects compared to patients taking MS Contin (Mucci-LoRusso et al 1998).
Patients taking OxyContin experienced less hallucinations and dizziness (Mucci-LoRusso
et al 1998, Reder et al 366, Weinstein et al 1998) or scratching and itching
than those taking MS Contin (Mucci-LoRusso et al 1998).
This latter observation might be accounted for by the speculation that
oxycodone may have less propensity to stimulate histamine liberation than
morphine (Flacke et al 1987, Poyhia et al 1992).
Clinical practice has shown that oxycodone has less associated stigma
than morphine. Many healthcare providers and patients associate morphine, but
not oxycodone, with advanced illness, impending death, and high risk of
addiction (Fitzmartin and Reder 1995). In
the United States, combinations of oxycodone plus acetaminophen or aspirin have
been used for years as Step 2 opioids for moderate chronic pain and moderate to
severe acute pain resulting in greater familiarity and comfort with prescribing
and taking oxycodone than morphine (Reder and Fitzmartin 1995, Levy 1996,
Caldwell et al 1999). OxyContin's
freedom from acetaminophen or aspirin facilitates upward dose titration and its
12-hour duration provides a significant patient convenience over 4-hourly
immediate-release opioids. OxyContin
has been shown to decrease pain and improve function in osteoarthritis (Caldwell
et al 1999, Roth et al 2000), post-herpetic neuralgia (Watson and Babul 1998),
major surgery (Sunshine et al 1996), and degenerative spine disease (Hale et al
2000)
In
summary, OxyContin is comparable and preferable to immediate-release oxycodone
for the control of chronic cancer pain. OxyContin
is comparable to MS Contin for the control of chronic cancer pain and is
approximately twice as potent as MS Contin on a milligram per milligram basis.
MS Contin is also effective for the control of osteoarthritis pain,
post-herpetic neuralgia, acute post-operative pain, and chronic low back pain. OxyContin has the attributes of an ideal opioid: short half
life, long duration of action, predictable pharmacokinetics, no clinically
significant active metabolites, rapid onset of action, easy titration, no
ceiling dose, minimal adverse effects, and minimal associated stigma (Evans
1999). Its multiple dosing forms
permit its early use and individualized titration to optimal comfort and
function in most patients with moderate to severe pain.
The benefit of OxyContin can be optimized by the use of immediate-release
oxycodone for breakthrough pain and would be greatly facilitated by wider access
to parenteral oxycodone for patients temporarily unable to use the oral route.
Its potential for less adverse side effects, relative to morphine, might be even
more advantageous for sicker patients with narrow therapeutic windows for opioid
analgesics.
OxyContin
Abuse: A Double Tragedy
The
rapidly escalating abuse of OxyContin in the last year is a double tragedy. The
first tragedy is the fact that individuals with the disease of addiction have
found a new substance to abuse that has a legal, pharmacy-based, distribution
system created by the needs of appropriate chronic pain patients and the
research and patient advocacy efforts of a legitimate, FDA-approved
pharmaceutical corporation. OxyContin
abuse by these individuals has led to violent crimes by these individuals and to
prescription diversion by deviant physicians and pharmacists to profit from
OxyContin's increased street value. The popularity of OxyContin abuse by addicts
has also resulted in the in the inadvertent deaths of first time drug abusers
who were not tolerant to opioids and were not aware of the relative potency of
the different formulations of OxyContin available.
The
second tragedy of OxyContin abuse is the fact that legitimate pain patients are
having increasing difficulty utilizing their appropriately prescribed OxyContin.
The extensive media coverage of OxyContin abuse has made patients afraid
of taking their OxyContin due to resurfacing of their concerns of addiction and
tolerance that had been accurately addressed by their physicians and nurses when
they received their first prescription. Patients
are also afraid of being victims of violent crime by addicts or dealers who want
their prescriptions or their OxyContin pills. The reduced stigma that oxycodone
once possessed compared to morphine has decayed.
Even when patients have their concerns about using OxyContin resolved by
their health care providers, they are being pressured by their friends, family,
and uninformed, health care professionals to stop using it.
Finally, as part of their efforts to reduce OxyContin abuse, pharmacies
and prescription benefit programs are restricting OxyContin sales, making it
increasingly difficult for honest patients to obtain ready access to their
appropriately prescribed, OxyContin.
Remedies
for OxyContin Abuse Must Not Interfere with Relief of Chronic Pain
Regulatory
agencies such as the FDA and DEA must take care not to increase the suffering of
chronic pain patients by reducing access to adequate supplies of legally
prescribed OxyContin in their efforts to control illegal OxyContin abuse.
Despite heroic efforts over the past twenty years by individual and
organizations to redress the balance of medicine and ensure appropriate
assessment and treatment of chronic pain, surveys still show that half of the
patients in this country with chronic pain are undertreated. Last year, the
Joint Commission on Accreditation of Healthcare Organizations (JCAHO) found it
necessary to develop new standards for pain control to address this system-wide
inadequacy. The National Cancer
Policy Board of the Institute of Medicine and the National Research Council
recently underscored the persistence of unrelieved suffering in patients with
advanced cancer and made specific recommendations to break down the barriers to
excellent palliative care (Foley and Gelband, 2001). The National Comprehensive Cancer Network and the American
Cancer Society have just released Cancer Pain Treatment Guidelines for Patients
to empower patients and their families to seek out and obtain state-of-the-art
cancer pain management. As an example of the increasing public expectation of
effective pain management, a California physician was just successfully sued for
failure to relieve his patient's chronic pain. Interventions aimed at reducing
the public problem of OxyContin abuse must not interfere with the safe and
effective use of OxyContin for the patient problem of unrelieved chronic pain.
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