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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 http://www.pharma.com/PI/ 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 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. JAm 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 mgq4h $3.12 Oxycodone 10 mgq4h $2.84 Hydrocodone 15 mgq4h $5.22 Methadone 10 mg bid $0.48 Source: http://www.walgreens.com/library/finddrug/ druginfosearch.jhtml. Accessed January 5, 2004. Controlled-Release Oxycodone 4 Journal of the American Academy of Orthopaedic Surgeons . 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. 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,. 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