Does therapeutic use of tapentadol cause false-positive urine screens for methadone or opiates?

To the Editor:

Tapentadol (Nucynta^®, Janssen Pharmaceuticals, Titusville, NJ) is a synthetic analgesic approved in the US in 2008.¹ Although mechanisms of action include mu opioid receptor agonism and serotonin reuptake inhibition, the drug is structurally similar to amphetamine. We previously found no false-positive urine amphetamine screens among patients taking therapeutic doses of tapentadol.² We froze the samples at − 80°C for future research.

In 2012, Collins et al. reported positive urine methadone screens using the DRI^® Methadone enzyme immunoassay (EIA) among patients taking tapentadol.³ We sought to determine whether therapeutic use of tapentadol is associated with false-positive urine screen for opiate or methadone by Syva EMIT II^® immunoassay.

We thawed the specimens before testing with the Siemens Syva EMIT II^® immunoassay for methadone and opiates. We confirmed all positive results by gas chromatography for methadone or liquid chromatography–tandem mass spectrometry (LC–MS/MS) for other opioids.

Aliquots from all specimens underwent quantitation of tapentadol and N-desmethyltapentadol by Mayo Medical Laboratories. After the addition of ammonium acetate buffer and beta-glucuronidase to liberate glucuronide-conjugated tapentadol and N-desmethyltapentadol, each sample underwent the LC–MS/MS method described by Coulter et al.⁴ For each analyte, the lower limit of quantitation is 50 ng/mL and the upper reporting limit is 50,000 ng/mL.

Table 1 shows the patients’ self-reported doses of tapentadol, EMIT results for methadone and opiates, confirmatory test results, active prescriptions, and quantitation of tapentadol and N-desmethyltapentadol.

Table 1. Patient characteristics and laboratory results.

Patient	Age (yrs)	Sex	Tablet size (mg)	Mean daily dose (mg/day)	Urine tapentadol (ng/mL)	Urine N-desmethyl tapentadol	EMIT methadone screen	EMIT opiate screen	Confirmatory testing result	Co-prescribed analgesic
1	64	F	100	150	> 50000	> 50000	Negative	Positive	Oxycodone	Oxycodone CR 80 mg BID
2	31	F	100	100	11500	2990	Negative	Negative
3	44	F	100	350	> 50000	> 50000	Negative	Negative
4	50	M	50	300	24900	4100	Negative	Positive	Hydrocodone	Norco 10/325 q4h PRN
5	37	M	100	500	> 50000	24500	Negative	Positive	Morphine	Morphine
6	50	F	75	450	28500	5320	Negative	Negative
7	54	F	50	50	14500	3880	Negative	Negative
8	41	M	100	200	> 50000	15000	Negative	Negative
9	86	F	50	100	44700	6640	Negative	Negative
10	55	F	50	150	41300	10200	Negative	Negative
11	33	F	100	600	> 50000	47900	Positive	Negative	Methadone	Methadone 40 mg qD
Median	50			200	44700	10200
Minimum	31			50	11500	2990
Maximum	86			600	> 50000	> 50000
Mean	49.5			268.2

Our results differ from those of Collins et al., who found frequent false-positive urine screens for methadone among patients taking tapentadol.³ The Collins study used the DRI Methadone EIA,⁵ a cloned enzyme donor immunoassay, which may have different performance characteristics from the Syva EMIT II immunoassay. They also used a lower threshold for methadone concentration of 130 ng/mL instead of the standard cutoff of 300 ng/mL. This lower threshold may increase the reported number of false-positive results. The Collins study did find cross-reactivity of tapentadol and its metabolites in concentrations reasonably achievable in the urine of patients with therapeutic use of tapentadol. Without knowing the total number of tapentadol-exposed patients or the number of patients from whom the false-positive methadone samples arose, one cannot estimate the test characteristics in the population of tapentadol-exposed patients.

All eleven patients in our study reported taking therapeutic doses of tapentadol between 50 and 600 mg/day (the range specified by the package insert)¹ with a median of 200 mg/day. About 99% of ingested tapentadol undergoes glucuronide conjugation (55%) and sulfate conjugation (15%) before excretion into the urine.^1,6 Our findings are consistent with study of a point-of-care immunoassay which showed no cross-reaction to tapentadol at 2,500 ng/mL.⁷ Our findings extend this range by showing no cross-reaction with the Syva EMIT II^® immunoassay at concentrations above 50,000 ng/mL.

No false-positive urine screens for methadone or opiate occurred using the Syva EMIT II^® immunoassay in urine samples from eleven patients with confirmed therapeutic use of up to 600 mg/day of tapentadol.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.