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 t
Trang 1Controlled-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%.2Absorption 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.3The 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.4,5Women 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 1:1.8.2Oxycodone 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 Registered 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
Trang 2severe 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.6Ninety-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.8Although 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.9In 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.10In 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).11In a study of acute pain man-agement in 150 dental patients with two or more
impact-ed molars, oxycodone 10 mg combinimpact-ed 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
Trang 3Drug 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.1Most 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 al13attempted 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 Research 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 160-160-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
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 http://www.pharma.com/PI/
Prescription/Oxycontin.pdf
Alan M Levine, MD, and Richard K Burdick, CRNP
Trang 4Although evidence exists that the use of CR oxycodone
has marked advantages for use in cancer-related pain
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
1 Miller NS, Greenfeld A: Patient characteristics and risk factors
for development of dependence on hydrocodone and
oxy-codone Am J Ther 2004;11:26-32.
2 Davis MP, Varga J, Dickerson D, Walsh D, LeGrand SB, Lagman
R: Normal-release and controlled-release oxycodone:
Pharma-cokinetics, pharmacodynamics, and controversy Support Care
Cancer 2003;11:84-92.
3 Mandema JW, Kaiko RF, Oshlack B, Reder RF, Stanski DR:
Charac-terization and validation of a pharmacokinetic model for
controlled-release oxycodone Br J Clin Pharmacol 1996;42:747-756.
4 Benziger DP, Kaiko RF, Miotto JB, Fitzmartin RD, Reder RF,
Chasin M: Differential effects of food on the bioavailability of
controlled-release oxycodone tablets and immediate-release
oxycodone solution J Pharm Sci 1996;85:407-410.
5 Package insert from OxyContin Source: http://www.pharma.
com/PI/Prescription/Oxycontin.pdf Accessed January 5, 2005.
6 Hale ME, Fleischmann R, Salzman R, et al: Efficacy and safety
of controlled-release versus immediate-release oxycodone:
Randomized, double-blind evaluation in patients with chronic
back pain Clin J Pain 1999;15:179-183.
7 Luo X, Pietroban R, Hey L: Patterns and trends in opioid use
among individuals with back pain in the United States Spine
2004;29:884-891.
8 Roth SH, Fleischmann RM, Burch FX, et al: Around-the-clock, controlled-release oxycodone therapy for osteoarthritis-related
pain: Placebo-controlled trial and long-term evaluation Arch
Intern Med 2000;160:853-860.
9 Watson CP, Moulin D, Watt-Watson J, Gordon A, Eisenhoffer J: Controlled-release oxycodone relieves neuropathic pain: A
ran-domized controlled trial in painful diabetic neuropathy Pain
2003;105:71-78.
10 Sinatra RS, Torres J, Bustos AM: Pain management after major
orthopaedic surgery: Current strategies and new concepts J Am
Acad Orthop Surg 2002;10:117-129.
11 Cheville A, Chen A, Oster G, McGarry L, Narcessian E: A ran-domized trial of controlled-release oxycodone during inpatient
rehabilitation following unilateral total knee arthroplasty J Bone
Joint Surg Am 2001;83:572-576.
12 Gammaitoni AR, Galer BS, Bulloch S, et al: Randomized, double-blind, placebo-controlled comparison of the analgesic efficacy of oxycodone 10 mg/acetaminophen 325 mg versus
controlled-release oxycodone 20 mg in postsurgical pain J Clin
Pharmacol 2003;43:296-304.
13 Katz NP, Sherburne S, Beach M, et al: Behavioral monitoring and urine toxicology testing in patients receiving long-term
opi-oid therapy Anesth Analg 2003;97:1097-1102.
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 mg q 4 h $3.12
Oxycodone 10 mg q 4 h $2.84
Hydrocodone 15 mg q 4 h $5.22
Methadone 10 mg bid $0.48
Source: http://www.walgreens.com/library/finddrug/
druginfosearch.jhtml Accessed January 5, 2004.
Controlled-Release Oxycodone