Oxycodone to Oxymorphone Metabolism

 

By Jennifer Schneider, M.D. and Ashley Miller

Practical Pain Management 7:71-73, 2007

 

Abstract:

Oxymorphone is a minor metabolite of oxycodone. Chronic pain patients treated with sustained- and/or immediate-release oxycodone (dosage range 15-730 mg/day), were tested for both oxycodone and oxymorphone by urine drug testing (UDT). None of the patients were being treated with oxymorphone. Among urines which tested positive for oxycodone by enzyme immunoassay (EIA), 80 out of 86 (93%) were also positive for oxymorphone.  Among 48 urine specimens subjected to quantitative analysis by gas chromatography/mass spectrometry (GC/MS), the ratio of oxymorphone to oxycodone in the urine ranged from 0% to 184%. There was no correlation between the dose of oxycodone and the ratio of oxymorphone to oxycodone. Urine drug screening by immunoassay of patients treated with oxycodone can be expected to be positive for oxymorphone, and the quantity of oxymorphone determined by GC/MS can at times equal or exceed that of oxycodone.

 

Introduction

Primary care physicians, as well as pain specialists, are increasingly ordering urine drug tests as part of the initial evaluation and follow-up of patients with chronic pain when opioid therapy is being used or is under consideration. Physicians should know that ordering a urine drug test (UDT) carries with it an obligation to understand the results and to act on them accordingly, instituting changes in treatment plan if indicated.

 

            Interpreting UDT results can be confusing unless physicians understand the metabolism of opioids.  For example, it is well recognized that codeine is a pro-drug, its analgesic effect resulting from conversion of codeine to morphine by the cytochrome P450 2D6 (Braithwaite et al, 1995; Gourlay et al 2004).  Thus, patients on codeine frequently test positive for both codeine and morphine.   (When patients who lack the cytochrome P450 2D6 enzyme necessary to convert codeine to morphine are treated with codeine, their urine may show only codeine [Gourlay et al, 2004]).  On the other hand, a finding of codeine in the urine of a patient being treated with morphine implies that the patient was also obtaining codeine from another source.  Similarly, hydrocodone is metabolized to hydromorphone, so that both may legitimately be found in the urine of a patient who is being prescribed hydrocodone (Vicodin, Lorcet, etc. (Gourlay et al, 2002; Heit & Gourlay, 2004).  But again, the reverse is not true; a patient prescribed hydromorphone (Dilaudid) should not have hydrocodone in the urine.  Recently, Cone et al (2006) reported that in some patients chronically treated with morphine, hydromorphone can appear in the urine as a result of a minor metabolic pathway. 

            An extended-release oxymorphone (OpanaER) and an immediate-release oxymorphone (Opana) have recently become available. The question then arises, what is the explanation for a finding of oxymorphone in the urine of a patient who is not being prescribed this drug?  Oxycodone is metabolized in part by cytochrome P450 2D6 to oxymorphone, which represents less than 15% of the total administered dose (Lalovic B et al, 2004). However, oxymorphone has a significantly longer half life (7-9 hours) (Endo patient package insert) than does oxycodone, whose mean elimination half-life following a single, oral dose is 3.51 ± 1.43 hours (Lalovic B et al, 2006). It is therefore plausible that in oxycodone-using patients, serum and urine levels of oxymorphone may be more than 15% those of oxycodone.  Large numbers of patients consume oxycodone, either as the extended-release form (OxyContin) or as immediate-release Percocet, Percodan, or its generic equivalents.  The present study was designed to obtain information on the frequency and concentration (in ng/mL) of oxymorphone in the urine of patients prescribed oxycodone.

 

Methods:

Over a two-month period (March and April 2007), all 175 patients in a chronic pain practice were asked without advance notice to submit a urine specimen. The patients were being treated for various types of chronic non-cancer pain, with back pain being the most common diagnosis.  Eighty-eight patients who were being prescribed oxycodone (extended-release and/or immediate-release) were tested for oxycodone and oxymorphone by an enzyme immunoassay (EIA). Because the usual immunoassay screen for opiates will not pick up oxycodone and oxymorphone, the order was written as “Routine urine drug test plus oxycodone and oxymorphone. Each patient’s daily dose and time of last dose were recorded by the medical assistant, who also checked the temperature of the urine immediately after voiding to be sure it fell within the range of 90-100 degrees F. Two of the patients had UDT results that were negative on immunoassay for oxycodone.  They were excluded from the remainder of this study. For 48 of the remaining 86 patients who tested positive for oxycodone on immunoassay, the urine concentration of oxycodone and oxymorphone was determined quantitatively using gas chromatography/mass spectrometry (GC/MS).  The cut-off level for a “Positive”  oxycodone or oxymorphone  result was 100 ng/mL.

 

Results:  

Of eighty-six patients whose urines were positive for oxycodone by EIA screen, 80 (93%) were also positive for oxymorphone.  The cut-off for the immunoassay screens was 100 ng/ml of oxycodone and 100 ng/ml of oxymorphone.  The six patients who were negative for oxymorphone on immunoassay screen were receiving only relatively small doses of oxycodone ranging from 15 to 45 mg per day.  Two of these patients were also tested by GC/MS, and one of the two was positive at a low level by this more sensitive test, which showed a urine level of oxymorphone of 66 ng/ml, below the cutoff of 100 ng/mL of the immunoassay.  It was also noted that 22 other patients on the same dose range of oxycodone  screened positive for both oxycodone and oxymorphone by immunoassay).

            Table 1 summarizes the daily doses of oxycodone  (sustained-release and/or immediate release) of the 86 patients. 

           

Table 1  Daily Oxycodone doses in the 86 patients

 

 

 

Dose q d

N (total 86)

% of 86    

15-100 mg

45

52.3%

101-200 mg

17       

19.8%         

201-300 mg  

12       

13.9%     

301-400 mg

7

8.1%

>400 mg

5

5.8%  

 

            The results for the quantitative GC/MS testing, in ng/mL, were widely variable, as expected because of the different doses as well as variable relationship between the time of the last dose and the time of urine collection. Accordingly the results are presented as a percentage of ng/ml oxymorphone to oxycodone  in the urine. Table 2 shows these results:

 

Table 2: Percent urine oxymorphone/oxycodone by CG/MS testing

in 48 patients on oxycodone

 

 

 

 

Dose q d

N=48         

%

Percent oxymorphone/oxycodone

15-50  mg

17

35.4%

0. 2.5, 3.3,3.5, 4.6, 9.8, 10.0, 10.6, 11.7 14.3, 15.2, 25.2, 34.1, 36.5, 41.1, 99.5, 138.9

51-100

11       

22.9%   

0.67, 7.6, 12.8, 13.2, 14.6, 14.6, 37.3, 71.9, 96.5, 96.9, 147.4

101-200 mg

7

14.6%

4.8, 5.8, 6.7, 13.7, 18.5, 19.4, 28.5

 

201-300 mg

6

12.5%

10.5, 11.6, 11.6, 19.1, 19.8, 184.1

>301 mg

7

14.6%,         

5.2, 5.5, 10.0, 14.7, 17.8 26.0, 45.8          

 

Table 2 clearly shows that there is tremendous variation in the relative amount of oxymorphone in the urine, as compared with oxycodone.  It does not appear as if higher doses are associated with a relatively greater percent of oxymorphone.  For the reader’s interest, the results for the five highest ratios are presented in Table 3.         

 

Table 3: Results in patients with high percent urine oxymorphone

 

 

 

 

Oxycodone dose qd          

oxymorphone (ng/ml) 

Oxycodone (ng/ml) 

%OM/OC

40 mg  

916     

912     

99.5%

50 mg

450    

324    

138.9

80 mg

2,406 

2,482 

96.9

80 mg

4,634 

4,802 

96.5

240 mg

4,436 

2,410 

184.1

 

Discussion

Physicians who obtain urine drug tests on their chronic patients need to be able to interpret the results and act on them when the results are unexpected.  If this is not done, the physician may fail to recognize drug misuse in the patient, or, alternatively, may unfairly accuse the patient of obtaining prescription opioids from other sources.

            To understand urine drug testing, physicians must have a basic understanding of the different types of tests. Standard screening tests, usually done by immunoassay, test only for the presence of classes of drugs (such as opiates and benzodiazepines.) The usual immunoassay for “opiates” reacts only with natural opiates (morphine, hydrocodone, hydromorphone, and codeine). Oxycodone, and oxymorphone can be identified by immunoassay, but only if those drugs are specifically requested.  To identify specific drugs and their concentration in the urine, labs offer gas chromatography/mass spectrometry (GC/MS) or high-performance liquid chromatography (HPLC).  Unexpected positive and negative results should be confirmed by one of these quantitative techniques.

Given the fact that various prescribed opioids can be metabolized to other opioids, urine drug test results can be confusing.  The physician needs to be familiar with the various metabolic pathways, and to be willing to contact laboratory personnel or more knowledgeable colleagues if unexpected results are found.  Because of the recent availability of oxymorphone, it behooves physicians to understand the significance of finding oxymorphone in the urine.  Patients who are being prescribed oxycodone can be expected to have oxymorphone in the urine. As this study shows, the amount of oxymorphone in the urine is highly variable. Even when the ratio was very high, the author had no reason to suspect that any of the patients were surreptitiously using oxymorphone in addition to their oxycodone.

 

Conclusion

Although oxymorphone is considered a minor metabolite of oxycodone, it may be found in the urine of patients prescribed only oxycodone in relatively large amounts compared with oxycodone. On the other hand, patients who are prescribed oxymorphone but not oxycodone would not be expected to have any oxycodone in their urine.  Knowledge of these facts will enable oxycodone and oxymorphone prescribers to interpret more correctly the results of urine drug screens.

 

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I would like to thank Drs. Howard Heit and Raju Hajela for reviewing this manuscript.