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Controlled-Release Oxycodone
Alan M. Levine, MD, and Richard K. Burdick, CRNP
The controlled-release (CR) form of oxycodone (Oxy-
Contin; Purdue Pharma, Stamford, CT) has become ex-
ceedingly popular as an effective analgesic, especially
for cancer-related pain. Because it can be taken twice
daily, it increases compliance and provides more effec-
tive relief by eliminating the need to “catch up” with the
pain. Some studies have demonstrated the value of the
CR formulations for both postoperative and chronic
pain control. When used in patients with chronic pain,
oxycodone has the potential for abuse; additionally, pa-
tients who are chronically using the medication who un-
dergo surgery may have a reduced therapeutic margin.
For patients with musculoskeletal conditions such as
chronic back and joint pain, as well as for postoperative
pain management, the efficacy of CR oxycodone must be
balanced with the potential risks of its use. These risks
differ from those of shorter acting narcotics. In 2000, the
number of first-time users of opiate pain relief reached
2 million. Survey data from the Drug Abuse Warning
Network indicate that OxyContin has become one of the
most commonly prescribed opiate medications; emer-
gency departments cite a 239% increase in use from 1996
to 2000.
1
Structure and Mechanism of Action
Oxycodone is a 4, 5-epoxy-14-hydroxy-3-methoxy-17-
methylmorphinan-6-one hydrochloride, which has dif-
ferent pharmacokinetics and opioid receptor binding
properties from morphine (Fig. 1). CR oxycodone is a

pure opioid agonist whose primary therapeutic modal-
ity is analgesia. The mechanism of action of the analge-
sic effect is still unknown. However, it acts on the cen-
tral nervous system, probably in opioid receptors for
endogenous compounds that occur in both the brain and
spinal cord. Oxycodone depresses the cough reflex by di-
rect action on the cough center in the medulla and causes
respiratory depression by acting directly on the respira-
tory centers in the brain stem. It also acts on smooth-
muscle tone in the stomach and duodenum and decreas-
es peristalsis in the colon. Finally, oxycodone can cause
release of histamine with or without vasodilation, thus
producing pruritus, flushing, and hypotension as side
effects.
Pharmacokinetics
Bioavailability of oral oxycodone in humans is approx-
imately 50%.
2
Absorption of immediate-release (IR) oxy-
codone is monoexponential, and maximum serum con-
centrations are achieved in about 1 hour. In the first pass
through the liver, some is metabolized into oxymorphone
(active) and noroxycodone (inactive), which are excreted
unchanged in the urine. CR oxycodone has different ab-
sorption properties than does IR oxycodone. The CR drug
is absorbed in a biexponential manner, starting with a
rapid phase of 37 minutes, which accounts for approx-
imately 40% of the dose, followed by a slower phase with
a half-life of slightly more than 6 hours, which accounts
for the remaining 60% of the total dose.

3
The time to max-
imum concentration is about 3.5 hours. The bioavailabil-
ity is roughly similar to that of immediate-release oxy-
codone except that the IR formulation has delayed
absorption but increased ultimate bioavailability after
high-fat meals. This effect is not seen in the CR formu-
lation except as a higher peak plasma concentration af-
ter use of 160-mg tablets.
4,5
Women and the elderly have
the highest area-under-the-curve (AUC) values and the
greatest drug effect. The bioavailability of CR oxycodone
is higher than that of CR morphine, and the relative po-
tency is about 1:1.8.
2
Oxycodone is excreted primarily by
the kidney in a variety of forms. Therefore, patients with
Dr. Levine is Director, Alvin and Lois Lapidus Cancer Institute, Sinai Hos-
pital of Baltimore, Baltimore, MD. Mr. Burdick is Certified Register ed Nurse
Practitioner, Division of Orthopaedic Oncology , Alvin and Lois Lapidus Can-
cer Institute, Sinai Hospital of Baltimore.
None of the following authors or the departments with which they are
affiliated has received anything of value from or owns stock in a commercial
company or institution related directly or indirectly to the subject of this
article: Dr. Levine and Mr. Burdick.
Reprint requests: Dr. Levine, Sinai Hospital, 2401 West Belvedere Avenue,
Baltimore, MD 21215.
Copyright 2005 by the American Academy of Orthopaedic Surgeons.
J Am Acad Orthop Surg 2005;13:1-4

Advances in Therapeutics and Diagnostics
Vol 13, No 1, January/February 2005 1
severe renal dysfunction (creatinine clearance <60 mL/
min) or severe hepatic impairment show peak plasma con-
centrations and AUC values 50% or higher than do nor-
mal individuals.
5
Indications for Use
Experience with the long-term use of CR opioids in the
treatment of cancer-related pain has been relatively fa-
vorable. This has led some to reassess the use of opi-
oids, and especially CR formulations, in the treatment of
chronic moderate and severe noncancer pain. In a ran-
domized short-term study (14 days) of 57 patients with
chronic back pain, CR oxycodone was compared with IR
oxycodone with a dose limit of 40 mg twice per day. Two
patients were discontinued because their pain was not
controlled at the dose limit; eight were discontinued (six
CR, two IR) for side effects including nausea, vomiting,
or dizziness. The average daily dose required was no dif-
ferent (40 mg CR and 38.5 IR). On a scale of 0 to 3 (no
pain to severe pain), pain intensity went from 2.5 (0.1 SE)
to 1.2 with CR and 1.1 with IR.
6
Ninety-three percent of
the patients reported side effects; 90% stated that side ef-
fects were mild or moderate. The discontinuance rate of
23% (13/57) is similar to that of other narcotics, such as
CR morphine and dihydrocodeine. Because the study was
short term, the authors stated that they could not address

issues surrounding long-term use of opioids. Few ran-
domized prospective studies have evaluated the use of
chronic opioid therapy in patients with low back pain.
Most that exist are short term, with little definitive ev-
idence of long-term effects.
7
Pain related to severe osteoarthritis has been shown
to contribute to disability and negatively affects physi-
cal functioning, mood, and sleep patterns. In a study of
patients with severe osteoarthritis pain, placebo was com-
pared with 10 mg and 20 mg bid doses of CR oxycodone.
There was a high rate of early discontinuance from the
trial (52.6% of the placebo and 10-mg groups) related to
ineffective treatment and to adverse effects (eg, nausea,
vomiting, somnolence). In the short-term phase of the tri-
al, the use of CR oxycodone 20 mg bid was statistically
superior to placebo (P > 0.05) in reducing pain as well as
improving mood, sleep, and physical functioning. In the
long-term phase of the trial with a fixed dose of 40 mg/d,
58 patients remained after 6 months of treatment but only
15 after 18 months.
8
Although CR oxycodone appears to
be effective for long-term symptomatic relief from osteoar -
thritis, side effects seem to limit the duration of useful-
ness.
CR oxycodone also has been evaluated in patients with
painful diabetic neuropathy. In a randomized double-
blind crossover study, it was compared with an active
placebo (benztropine) that mimics the side effects of opi-

oids. There was a 67% decrease in pain scores (visual an-
alog scale) with the CR formulation versus a 28% decrease
from baseline with placebo (P > 0.00001), as well as im-
provements in the quality-of-life domains on the Med-
ical Outcomes Study 36-Item Short Form.
9
In an open-
label component of the study that lasted for a year,
escalation of dose to maintain pain control was neces-
sary in approximately 30% of patients.
Regarding the use of CR oxycodone for postoperative
pain for orthopaedic surgical procedures, it has been
suggested that CR formulations be used as a transition
from both patient-controlled and epidural analgesia
but not given when either is still being used.
10
In a study
of pain relief after surgery for anterior cruciate ligament
reconstruction, CR oxycodone was compared with IR
oxycodone given both on a schedule and as needed.
The group receiving CR oxycodone required less
total dose and had better analgesia with fewer side
effects.
10
In another study of postacute pain management done
at the time of transfer to a rehabilitation facility, patients
who had undergone total knee arthroplasty were random-
ized to CR oxycodone or to placebo (plus IR oxycodone
for breakthrough pain). Those on CR had less pain, sig-
nificantly (P < 0.001) greater range of motion and quad-

riceps strength, and earlier discharge from rehabilitation
by 2.3 days (P < 0.013).
11
In a study of acute pain man-
agement in 150 dental patients with two or more impact-
ed molars, oxycodone 10 mg combined with acetamin-
ophen 325 mg produced better results than did 20 mg of
CR oxycodone, with 24.5% fewer patients reporting side
effects.
12
Figure 1 Chemical structure of controlled-release oxycodone.
(Reproduced with permission from Purdue Pharma, Stamford, CT.)
Controlled-Release Oxycodone
2 Journal of the American Academy of Orthopaedic Surgeons
Drug Interactions and Adverse Effects
Breaking, crushing, or chewing OxyContin tablets de-
stroys the CR mechanism and may result in a potentially
fatal overdose. The most common side effects are con-
stipation, nausea, and somnolence, which occur in
about 25% of patients. Pruritus, dizziness, and vomiting
occur in an additional 15%. Headache, dry mouth,
sweating, and orthostatic hypotension are less com-
mon.
5,6
Risk of developing opioid dependency and addiction
is related to a patient’s previous history of substance abuse
or polymedication use. Caution should be observed in
combination use with MAO inhibitors as well as with var-
ious other central nervous system depressants, includ-
ing sedatives, hypnotics, phenothiazines, antiemetics,

tranquilizers, and alcohol.
In addition to dependency and addiction, interactive
effects can lead to respiratory depression, hypotension,
profound sedation, or coma. In such a situation, a re-
duction in the starting dose of OxyContin should be
considered.
A Drug Enforcement Administration survey of oxy-
codone/OxyContin–related deaths from 2000 to 2001, in-
volving 775 medical examiners in 32 states, found 949
verified deaths from oxycodone; 49% were attributed spe-
cifically to OxyContin.
1
Most deaths were associated with
multiple drug use. Of those drugs found, 40% contained
benzodiazepines, 40% contained an opiate in addition to
oxycodone, 30% contained an antidepressant, 14% con-
tained over-the-counter antihistamines or cold medica-
tions, and 15% were positive for cocaine or its metabo-
lite. Also noted was that, of the 464 deaths linked to
OxyContin, only 88 were associated with quantifiable lev-
els of alcohol.
1
Accurately identifying patients with potential for abuse
may be difficult. Katz et al
13
attempted to identify patients
with addiction by reviewing chronic noncancer pain pa-
tients treated in two centers; they found that 29% of sub-
jects had urine toxicology screens that were inconsistent
with their prescribed medications and that 22% had be-

havioral changes.
Of 24.7 million people claiming back pain in 1999,
12.6% had at least one prescription for an opioid drug.
Previous guidelines published by the Agency for Health-
care Resear ch and Quality recommended against the long-
term use of opioids for back pain in consideration of short-
course opioids as an alternative therapy.
7
Another major concern is the potential development
of drug tolerance, which may lead to increasing drug dos-
ages and, eventually, to dependency or addiction. How-
ever, opinions vary, and some physicians and clinical re-
searchers think that drug tolerance generally does not
develop in patients with stable pain pathology.
7
Conversion Factors
Postoperative conversion to oral OxyContin can be
achieved by multiplying the amount of intravenous mor-
phine used in the previous 24 hours by a conversion factor
of 1.5 to 3, depending on the intravenous morphine
dosage used. Other conversion factors are displayed in
Table 1.
Cost and Dosage
CR oxycodone is available in 10-, 20-, 40-, 80-, and 160-
mg tablets. The use of 80- and 160-mg tablets should
be carefully monitored because of the potential for
respiratory depression and the increased peak serum
levels noted with these two dosages after ingestion of a
fatty meal. The formulation is specific for use at 12-hour
intervals, and more frequent or as-needed use is not

recommended.
IR 5-mg oxycodone can be used for breakthrough pain,
with the CR dosage modified based on the amount of
daily IR formulation used over the course of a week. Drug
cost versus dosing also can be a factor in choosing CR
formulations (Table 2).
Table 1
Multiplication Factors for Converting the Daily
Dose of Prior Opioids to the Daily Dose of Oral
Oxycodone*
(mg/day Prior Opioid x Factor
= mg/day Oral Oxycodone)
Drug
Oral Prior
Opioid
Parenteral Prior
Opioid
Oxycodone 1 —
Codeine 0.15 —
Hydrocodone 0.9 —
Hydromorphone 4 20
Levorphanol 7.5 15
Meperidine 0.1 0.4
Methadone 1.5 3
Morphine 0.5 3
* To be used only for conversion to oral oxycodone. For pa-
tients receiving high-dose parenteral opioids, a more conserva-
tive conversion is warranted. For example, for high-dose
parenteral morphine, use 1.5 instead of 3 as a multiplication
factor.

Reproduced with permission from the package insert for
OxyContin. Available at />Prescription/Oxycontin.pdf
Alan M. Levine, MD, and Richard K. Burdick, CRNP
Vol 13, No 1, January/February 2005 3
Summary
Although evidence exists that the use of CR oxycodone
has marked advantages for use in cancer-related pain con-
trol, the benefits are less apparent for musculoskeletal con-
ditions. For chronic conditions, such as joint or back pain,
the benefits of chronic opioid therapy even with CR for-
mulations are less clear. Most published studies show ef-
fectiveness only in short-term trials when compared with
placebo. With longer term open-label studies, the inci-
dence of side effects may limit usefulness. Additionally,
the potential need to escalate dosage increases both side
effects and the potential for addiction in susceptible in-
dividuals with known risk factors. Identifying patients
with addiction and behavioral changes can be difficult.
In addition, patients with osteoarthritis or back pain who
are on large doses of CR oxycodone may have a very small
therapeutic margin for postoperative pain control if they
need to undergo surgery. Finally, for postoperative pain
control, a CR formulation may be helpful for short-term
use when converting from patient-controlled or epidu-
ral analgesia. However, in most cases, for postoperative
pain management, a lower total opioid dose can be sim-
ilarly efficacious, with fewer or lessened side effects, when
an oxycodone-acetaminophen formulation is used.
References
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Table 2
Drug Comparison, Dose, and Price for a 24-Hour
Period
Drug Dose 24-Hour Dose
Duragesic patch 50 µg q 72 h $9.30
OxyContin 30 mg bid $9.14
MS Contin 45 mg bid $6.42
Hydromorphone 4 mgq4h $3.12
Oxycodone 10 mgq4h $2.84
Hydrocodone 15 mgq4h $5.22
Methadone 10 mg bid $0.48
Source: />druginfosearch.jhtml. Accessed January 5, 2004.
Controlled-Release Oxycodone
4 Journal of the American Academy of Orthopaedic Surgeons