Oxycodone accumulation in a hemodialysis patient.

Abstract: Oxycodone and oxycodone-containing analgesics are often used for the relief of pain. In the presence of renal dysfunction, the half-life of oxycodone and metabolites can be prolonged. We describe the case of a 41-year-old chronic hemodialysis patient who received multiple doses of oxycodone/acetaminophen resulting in accumulation of the medication and consequent lethargy, hypotension and respiratory depression. These adverse effects were reversed with multiple bolus doses of naloxone, followed by a continuous infusion administered for 45 hours. Utilizing the Naranjo probability scale, the patient had a "probable" adverse drug reaction to the oxycodone. Oxycodone should be used with caution in patients with chronic renal failure.

Key Words: oxycodone, opioids, renal failure, hemodialysis, toxicity

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Oxycodone, a semisynthetic opioid and congener of morphine, is commonly used for pain relief. All natural occurring and semisynthetic opioid analgesics are derivatives of opium. Opium is the dried and powdered form of the juice that is harvested from the unripe seed capsules of the poppy plant (Papaver somniferum). There are five distinct chemical classes of alkaloids found in opium, one of which is the phenanthrene alkaloids. The three main phenanthrene alkaloids include morphine, codeine and thebaine. Oxycodone is structurally classified as a phenanthrene opioid analgesic, as it is a derivative of thebaine. (1) Oral administration of oxycodone is approximately 1.5 to 2 times more potent than oral morphine. (2,3)

Oxycodone's mechanism of action is similar to that of all opioid analgesics. Opioids exert their activities by binding to opioid receptors mainly within the central nervous system. Therapeutically, opioids are used to provide analgesia, as antitussives, and to treat symptoms of diarrhea. Other pharmacologic effects of opioids include effects on the central nervous system (sedation, respiratory depression, confusion, miosis), gastrointestinal tract (decreased peristalsis, constipation), and cardiovascular systems (orthostatic hypotension).

Orally administered oxycodone has a bioavailability of approximately 60 to 87% and is primarily excreted by the kidney. (4) Oxycodone is extensively metabolized and conjugated in the liver by both N-and O-demethylation and 6-ketoreduction. N-demethylation is the metabolic pathway for the end product noroxycodone. O-demethylation, catalyzed by the cytochrome P450 isoenzyme CYP2D6, is the metabolic pathway for the end product oxymorphone. (5) Noroxycodone is the main metabolite of oxycodone and is generally thought to be inactive. On the other hand, oxymorphone is a potent opioid analgesic which is roughly 30 times more potent than oral morphine. (2) Excretion of oxycodone and metabolites measured in the urine have been reported as follows: free oxycodone up to 19%, conjugated oxycodone up to 29%, free oxymorphone 0%, and conjugated oxymorphone [less than or equal to]14%. (6) Free and conjugated noroxycodone have been found in the urine but have not been quantified.

The half-life of oxycodone and metabolites can be prolonged in a patient with renal failure. We describe a chronic hemodialysis patient who received multiple doses of oxycodone/acetaminophen resulting in accumulation of the medication and consequent lethargy, hypotension and respiratory depression.

Case Report

A 41-year-old male was admitted to the hospital for an infected arteriovenous (AV) graft. An infectious disease physician was consulted and appropriate antibiotics were initiated. The patient's medical history was significant for end-stage renal disease requiring hemodialysis for many years, hypertension, coronary artery disease, peptic ulcer disease, anemia of chronic disease, renal bone disease, hyperparathyroidism and noncompliance.

The infected AV graft was removed on day one of admission and a permanent hemodialysis catheter was inserted on day two of admission. Preoperatively on day two, the patient received hydromorphone 1 mg IV and a continuous infusion of hydromorphone was initiated at 0.2 mg/h. Thirty minutes after the initiation of the hydromorphone, the patient experienced periods of apnea and respirations were 7 per minute. Naloxone 0.4 mg IV was administered. Oxycodone 5 mg/acetaminophen 325 mg one to two tablets every 4 to 6 hours as needed for pain was written for pain relief after the graft removal on day one. The oxycodone-containing medication was not administered until day two, after the hydromorphone was discontinued. On day 6, the permanent hemodialysis catheter, inserted on day 2 of admission, required removal due to poor blood flow. A new permanent hemodialysis catheter was inserted on day 8 of admission.

In addition, the patient experienced significant pain in his right great toe at the metatarsal phalangeal joint. Gout was suspected initially and colchicine was started on day 3 of admission. The symptoms did not resolve and the patient continued to have a significant amount of pain.

Over the course of the next 8 days, the patient received a total of 67 oxycodone 5 mg/acetaminophen 325 mg tablets for pain. On day 11 of admission, the patient became very lethargic, obtunded, unresponsive, and on examination had miosis and sluggish pupils. Naloxone 0.4 mg IV was administered and the patient responded immediately. The oxycodone 5 mg/acetaminophen 325 mg order was discontinued. Forty-five minutes later, the patient became somnolent again. The patient continued to have progressive decreased responsiveness, shallow respirations, dusky-colored skin and diaphoresis; he was subsequently transferred to the intensive care unit. In addition, the patient developed a fever, hypotension and respiratory depression. Naloxone 0.2 to 0.4 mg IV was administered when needed for increased lethargy and a phenylephrine drip was initiated to increase the blood pressure. The patient responded well to the naloxone, but as the naloxone's reversal of the opioid ceased, the decreased level of consciousness would return.

The patient received a total of 2.2 mg of naloxone over 10 1/2 hours before a naloxone drip was initiated at 0.25 mg/h. Throughout the night, the patient experienced bradycardia and intermittent sinus arrest secondary to sleep apnea and narcosis. The patient experienced up to a 6.7 second sinus arrest with the apnea episodes. The naloxone drip was titrated between 0.13 and 0.25 mg/h and was discontinued after 45 hours. The phenylephrine drip was weaned off 34 hours after it was initiated. The patient's pain scores were between 0 and 3 once the naloxone drip was initiated.

Nineteen days after admission, debridement of the toe was performed and a diagnosis of osteomyelitis was made.

Discussion

Poyhia et al, (7) in an oxycodone metabolism and pharmacokinetic study, found that over a 24-hour time period, 8 to 14% of the total oxycodone dose was excreted in the urine as conjugated and free oxycodone. In addition, oxymorphone was excreted mainly as a conjugate and noroxycodone was excreted mostly in an unconjugated form. Although oxymorphone is more potent than the parent oxycodone, it may not significantly affect the pharmacodynamics in patients with normal renal function. Kirvela et al (8) studied the pharmacokinetics of oxycodone in uremic patients undergoing renal transplant and found the elimination half-life of oxycodone was extended and excretion of metabolites was hindered in patients with end-stage renal disease. They concluded the impaired clearance was possibly due to alterations in hepatic blood flow and enzyme activity caused by the uremia. Benzinger et al (9) studied the area under the curve (AUC) of oxycodone, noroxycodone and oxymorphone in patients with renal failure and found they were increased by 60%, 50% and 40% respectively. The same research group found that this led to a one hour longer half-life of oxycodone compared with the normal controls. (10) The overall clinical effect of oxycodone or metabolite accumulation as a result of renal failure is unknown. Although there are no case reports of oxycodone use in renal failure causing adverse events, Fitzgerald (11) has anecdotally noted problems with CNS toxicity and sedation when typical doses of oxycodone were used in renal failure patients.

As the metabolism and excretion of both oxycodone and the metabolite oxymorphone is slowed by renal failure, there is the potential for altered pharmacodynamics of the drug. The elimination half-life is lengthened, resulting in the potential for rapid accumulation of the parent drug and active metabolites if normal dosing regimens are followed. In the case of multiple doses given over a relatively short period of time, opioid toxicity could develop resulting in confusion, delirium, sedation and possibly respiratory depression. As with all opioid analgesics, oxycodone dosing needs to be adjusted based on patient-specific pharmacokinetic factors such as absorption, metabolism and excretion while titrating for clinical response of analgesia or toxicities.

A review by Dean (12) on opioids in renal failure and dialysis concluded that there was insufficient data to make recommendations on the use of oxycodone in this patient population. Furthermore, this review suggests avoiding oxycodone in patients undergoing dialysis due to a paucity of data on the effect dialysis may have on oxycodone and metabolites. A subsequent case study report by Lee et al (13) found some evidence that hemodialysis may decrease plasma levels of oxycodone, noroxycodone and oxymorphone. However, there is no correlation with the plasma levels removed and clinical outcomes in regard to loss of efficacy or reduction of toxicity due to oxycodone or metabolites.

This is the first case report, to our knowledge, which demonstrates an accumulation of oxycodone and/or metabolites in a chronic hemodialysis patient, resulting in a decreased level of consciousness, hypotension and respiratory depression. The Naranjo scale is a method used to estimate the probability of adverse drug reactions. (14) This scale ranks the patient as having had a "probable" adverse drug reaction (score = 8).

Conclusion

Oxycodone/acetaminophen, a common medication utilized for pain control, may accumulate in patients with renal failure. In this case, a chronic renal failure patient received multiple doses of oxycodone/acetaminophen which resulted in accumulation of the oxycodone. The patient experienced lethargy, hypotension, and respiratory depression. A continuous infusion of naloxone was required to reverse the adverse effects of the oxycodone. Oxycodone should be used with caution in patients with chronic renal failure.

References

1. Schiff PL. Opium and its alkaloids. Am J Pharm Educ 2002;66:186-194.

2. American Pain Society. Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain. 5th ed. Glenview. IL, 2003.

3. Kaiko R, Lacouture P, Hopf K, et al. Analgesic onset and potency of oral controlled-released (CR) oxycodone and CR morphine (abstract). Clin Pharmacol Ther 1996;59:130.

4. Robson P. The use of opioids in palliative care patients with renal failure. Cancer Medicine 2004;2:40-48.

5. Heiskanen T, Olkkola KT, Kalso E. Effects of blocking CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone. Clin Pharmacol Ther 1998;64:603-611.

6. Baselt RC, Stewart CB. Determination of oxycodone and major metabolite in urine by electron-capture GLC. J Anal Toxicol 1978;2:107-109.

7. Poyhia R, Seppala T, Olkkola KT, et al. The pharmacokinetics and metabolism of oxycodone after intramuscular and oral administration to healthy subjects. Br J Pharmacol 1992;33:617-621.

8. Kirvela M, Lindgren L, Seppala T, et al. The pharmacokinetics of oxycodone in uremia patients undergoing renal transplantation. J Clin Anesth 1996;8:13-18.

9. Benziger DP, Cheng C, Miotto J, et al. Comparative pharmacokinetics of controlled release oxycodone (OxyContin) in special populations. In: Abstracts, 8th World Congress on Pain. IASP Press, Seattle, WA, 1996:285.

10. Kaiko R. Benziger D, Cheng C, et al. Clinical pharmacokinetics of controlled release oxycodone in renal impairment (abstract). Clin Pharmacol Ther 1996;59:130.

11. Fitzgerald J. Narcotic analgesics in renal failure. Conn Med 1991;55:701-704.

12. Dean M. Opioids in renal failure and dialysis patients. J Pain Symptom Manage 2004;28:497-504.

13. Lee MA, Leng ME, Cooper RM. Measurements of plasma oxycodone, noroxycodone andoxymorphone levels in a patient with bilateral nephrectomy who is undergoing haemodialysis. Palliat Med 2005;19:259-260.

14. Naranjo CA, Busto U, Sellers EM, et al. A method of estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-245.

Courage is very important. Like a muscle, it is strengthened by use.
--Ruth Gordon

Pamela A. Foral, PharmD, BCPS, Joseph R. Ineck, PharmD, and Kelly K. Nystrom, PharmD, BCOP 

From Alegent Health, Bergan Mercy Medical Center, and Creighton University, Omaha, NE.

Reprint requests to Pamela A. Foral, PharmD, BCPS, Creighton University School of Pharmacy and Health Professions. 2500 California Plaza, Omaha, NE 68178. Email: [e-mail]

Accepted June 21, 2006.

RELATED ARTICLE: Key Points

* Oxycodone-containing analgesics are often used for the relief of pain.

* Oxycodone accumulation in chronic renal failure resulting in lethargy, hypotension, and respiratory depression has not been previously reported.

* Oxycodone should be used with caution in patients with chronic renal failure.