Article - Huestis — USA v. Jittaphol (Dkt. 70-3, D. Mass.)

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U.S. District Court for the District of Massachusetts · No. 1:21-cr-10270-MLW · Doc. 70-3 · 2022-04-06 · Docket on CourtListener

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Journal of Analytical Toxicology, Vol. 24, October 2000 
Monitoring Opiate Use in Substance Abuse Treatment 
Patients With Sweat and Urine Drug Testing 
Marilyn A. Huestis 1,*, Edward J. Cone 1,t, Conrad J. Wong 2, Annie Umbricht 1, and Kenzie L. Preston 1 
I National Institute on Drug Abuse Intramural Research Program, Baltimore, Maryland and 2Department of Psychology, 
University of Vermont, Burlington, Vermont 
Abstract 
Although urine testing remains the standard for drug use 
monitoring, sweat testing for drugs of abuse is increasing, especially 
in criminal justice programs. One reason for this increase is sweat 
testing may widen the detection window compared to urine testing. 
Drug metabolites are rapidly excreted in urine limiting the window 
of detection of a single use to a few days. In contrast, sweat 
collection devices can be worn for longer periods of time. This study 
was designed to compare the efficacy of sweat testing versus urine 
testing for detecting drug use. Paired sweat patches that were 
applied and removed weekly on Tuesdays were compared to 3-5 
consecutive urine specimens collected Mondays, Wednesdays, and 
Fridays (355 matched sweat and urine specimen sets) from 44 
patients in a methadone-maintenance outpatient treatment 
program. All patches (N = 925) were extracted in 2.5 mL of solvent 
and analyzed by ELISA immunoassay for opiates (cutoff 
concentration 10 ng/mL). A subset (N = 389) of patches was 
analyzed by gas chromatography-mass spectrometry (GC-MS). 
Urine specimens (N = 1886) were subjected to qualitative analysis 
by EMIT (cutoff 300 ng/mL). Results were evaluated to (1) 
determine the identity and relative amounts of opiates in sweat; 
(2) assess replicability in duplicate patches; (3) compare ELISA and 
GC-MS results for opiates in sweat; and (4) compare the detection 
of opiate use by sweat and urine testing. Opiates were detected in 
38.5% of the sweat patches with the ELISA screen. GC-MS analysis 
confirmed 83.4% of the screen-positive sweat patches for heroin, 
6-acetylmorphine, morphine, and/or codeine (cutoff concentration 
5 ng/mL) and 90.2% of the screen-negative patches. The sensitivity, 
specificity, and efficiency of ELISA opiate results as compared to 
GC-MS results in sweat were 96.7%, 72.2%, and 89.5%, 
respectively. Heroin and/or 6-acetylmorphine were detected in 
78.1% of the GC-MS-positive sweat patches. Median 
concentrations of heroin, 6-acetylmorphine, morphine, and 
codeine in the positive sweat samples were 10.5, 13.6, 15.9, and 
13.0 ng/mL, respectively. Agreement in paired sweat patch test 
results was 90.6% by ELISA analysis. For the purposes of this 
comparison of ELISA sweat patch to EMIT urine screening for 
opiates, the more commonly used urine lest was considered to be 
the reference method. The sensitivity, specificity, and efficiency of 
* Author to whom correspondence and reprint requests should be addressed. Marilyn A. Huestis, 
Ph.D., Acting Chief, Chemistry and Drug Metabolism Section, Intramural Research Program, 
NIDA, NIH, 5500 Nathan Shock Drive, Baltimore, MD 21224. E-mail mhuestis@irp nida.nih.gov 
t Current address: ConeCbem Research, 44t FairtreeDrive, SevernaPark, MD. 
sweat patch results to urine results for opiates were 68.6%, 86.1%, 
and 78.6%, respectively. There were 13.5% false-negative and 
7.9% false-positive sweat results as compared to urine tests. 
Analysis of sweat patches provides an alternate method for 
objectively monitoring drug use and provides an advantage over 
urine drug testing by extending drug detection times to one week or 
longer. In addition, identification of heroin and/or 6-acetylmorphine 
in sweat patches confirmed the use of heroin in 78.1% of the 
positive cases and differentiated illicit heroin use from possible 
ingestion of codeine or opiate-containing foods. However, the 
percentage of false-negative results, at least in this treatment 
population, indicates that weekly sweat testing may be less sensitive 
than thrice weekly urine testing in detecting opiate use. 
Introduction 
The drug treatment, criminal justice, workplace, and military 
drug-testing programs have relied extensively on urine drug 
testing to monitor individuals' opiate use and to stem some of the 
problems associated with illicit drug use. Urine drug testing has 
become an established, reliable, standardized, relatively inexpen- 
sive, and widely available technology. One of the disadvantages of 
urine testing is the relatively short window of drug detection 
requiring frequent specimen collection to monitor drug use ade- 
quately. Furthermore, adulteration of urine specimens can be 
accomplished by adding a wide variety of chemical, and simply 
ingesting large quantities of water can lower drug concentrations 
below threshold limits. Careful monitoring of specimen collec- 
tion, sometimes including direct observation, may be necessary 
to prevent specimen adulteration. In addition, the ingestion of 
opiate-containing foods (poppy seeds) or licit opioid analgesics 
can produce positive urine opiate tests. This has complicated the 
interpretation of positive opiate tests and contributed to the 
recent federally mandated increase in the opiate cutoff concen- 
tration from 300 ng/mL to 2000 ng/mL and the addition of 6- 
acetylmorphine confirmation to identify heroin abuse. In 
response to these issues, and because of the unique information 
provided from monitoring drugs in alternative biological 
matrices, testing of drugs of abuse in sweat, saliva, and hair has 
gained increased importance. 
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Sweat is an alternative matrix for drug testing that may provide 
an additional tool for monitoring drug use. A number of drugs of 
abuse have been found to be secreted in sweat including 
methadone (1,2), amphetamines (3-7), methamphetamine 
(4,6,8-10), alcohol (8), morphine (2,8,11,12), heroin (7,13), cocaine 
(2,7,13-18,19), nicotine (11), and marijuana (7,11). In addition, 
sweat on clothing has been used to detect drugs for forensic pur- 
poses (8,12,20). A promising method for routine sweat collections 
appears to be the sweat patch (13,14,21). Our laboratory has 
recently demonstrated the utility of sweat patches for monitoring 
cocaine use in a treatment population. This paper reports the 
results of sweat testing for opiate use in the same population. The 
sweat patch device consists of an adhesive layer on a thin trans- 
parent film of surgical dressing and a rectangular, absorbent, cellu- 
lose pad (14 cm2). The surgical dressing film allows oxygen, carbon 
dioxide, and water vapor to escape, whereas the nonvolatile con- 
stituents in sweat are retained in the absorbent pad. Sweat patches 
are applied to the torso or arm after cleansing of skin with an 
alcohol wipe to prevent contamination and improve adherence. 
The patches are tamper resistant; they have identifying serial num- 
bers and once removed cannot be reapplied to the skin. Because the 
patches are worn for one week, the window of detection can be 
longer than that provided by urine testing. 
Limited data are available on the identity and concentration of 
opiate analytes secreted in sweat following administration of 
heroin, morphine or codeine from controlled-dosing studies. An 
immunoassay for opiates was first used to document the presence 
of morphine in sweat after 10-rag oral doses of morphine (8). More 
than 15 years later, heroin and 6-acetylmorphine, but not mor- 
phine, were detected in all (N = 6) sweat patches collected up to 
120 h after a single 20 mg intravenous dose of heroin to two 
human subjects (13). Heroin was the primary analyte detected in 
sweat in the first 24-h patch, but concentrations decreased in 
sweat patches worn for longer periods of time, suggesting heroin 
hydrolysis in the patch. In another study, codeine (90 mg) was 
orally administered to six subjects and sweat was collected with 
the PharmChek TM Sweat Patch over the following six days (22). 
Codeine was detected in sweat within 1 h, peak secretion occurred 
between 12 to 24 h, and concentrations remained relatively stable 
from 48 to 144 h. A fivefold variation in peak codeine concentra- 
tion was noted between subjects and up to a threefold variation in 
patches worn by the same subject on different areas of the body. 
Morphine was not detected in any patch (limit of detection = 0.5 
ng/patch). Codeine secretion in sweat measured for up to 24 h in 
six subjects after oral administration of 60 mg codeine sulfate con- 
firmed the early appearance of codeine in sweat (1 h) with peak 
concentrations between 4 and 24 h (23). 
Sweat patches have also been used to monitor opiate use in out- 
patient drug-treatment settings. Heroin, 6-acetylmorphine, and 
morphine were detected in 17 sweat patches collected from 
known heroin users admitted to the Haight Ashbury Free Clinic 
in San Francisco (13). Heroin concentrations were greater than 
6-acetylmorphine concentrations in approximately half of the 
patches; there was no consistent ratio between the analytes. 
Furthermore, morphine concentrations exceeded 6-acetylmor- 
phine levels in about one-third of the patches. In a study of 20 
heroin users in a detoxification clinic, sweat patches worn for five 
days were analyzed for heroin, 6-acetylmorphine, morphine, and 
510 
Journal of Analytical Toxicology, Vol. 24, October 2000 
codeine by GC-MS or LC-MS (7). In the eight cases where heroin 
use was confirmed, 6-acetylmorphine was the primary analyte, 
with 6-acetylmorphine concentrations exceeding those of heroin 
and morphine, except in one instance. Codeine use was noted in 
four cases; codeine concentrations were 10 to 100 times greater 
than morphine concentrations in the sweat. In another study of 
methadone-maintenance patients, 6-acetylmorphine, morphine, 
and codeine, but not heroin, were detected in sweat patches worn 
for seven days by individuals abusing heroin (24). 
The present study evaluated the use of sweat patches for moni- 
toring opiate use in a drug-abuse treatment population (19,25). 
Duplicate patches were applied to methadone-maintenance 
patients participating in a clinical trial of a behavioral treatment 
for drug abuse. Patches were worn for one week, removed, and 
analyzed by ELISA immunoassay and GC-MS for the presence of 
opiates. Urine specimens collected over a similar timeframe were 
analyzed for opiates by EMIT immunoassay. Results were evalu- 
ated to (1) determine the identity and relative amount of opiates 
in sweat; (2) assess replicability in duplicate patches; (3) compare 
two methods (ELISA and GC-MS) of assaying opiates in sweat; 
and (4) compare the detection of opiate use by sweat and urine 
drug testing. 
Methods 
Participants 
The participants were 44 patients (29 male, 15 female; 20 
African American, 24 Caucasian)who were recruited from among 
participants in a clinical trial of a behavioral treatment for cocaine 
and heroin abuse (25). Individuals were eligible for the primary 
treatment study if they were between the ages of 18 and 65, if they 
qualified for methadone maintenance according to the Food and 
Drug Administration guidelines, and if they reported histories of 
intravenous opiate use. All patients received standard methadone- 
maintenance drug-abuse treatment throughout the study that 
included daily methadone (50 to 80 mg/day, oral) and weekly indi- 
vidual counseling. The NIDA Institutional Review Board for 
human research approved this study. All volunteers gave 
informed written consent prior to study participation and were 
paid $10/week for wearing sweat patches. Details of the experi- 
mental treatment procedures have been described (25). 
Specimen collection and analysis 
Volunteers could participate for a maximum of 18 weeks. 
Participants visited the clinic seven days per week to receive 
methadone. Urine specimens were collected on Monday, 
Wednesday, and Friday under direct observation by trained staff. 
Each specimen was analyzed for opiates (EMIT d.a.u. TM, Behring 
Diagnostics, San Jose, CA) with a cutoff concentration of 300 
ng/mL within 24 h of collection. 
Sweat patches were applied each Tuesday to the subject's lower 
abdomen and back after the skin was cleaned with an alcohol 
wipe. The study number, the subject's identification code 
number, patch code number, and the date of application were 
recorded on a 3 x 5-in. index card. The following Tuesday, prior to 
removing each sweat patch, technicians examined the patch to 
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Journal of Analytical Toxicology, Vol. 24, October 2000 
determine its condition. Patch condition was rated according to 
the following categories: I = intact patch; C = curling (edges); E = 
exposed patch edge; and M = missing patch. To remove patches, 
the technicians pulled the adhesive edge along the side of the 
patch. Once the adhesive along the side of the patch was away 
from the skin, the patch was pulled outward from both top cor- 
ners equally on both sides of the patch. Technicians were 
instructed to wear gloves and to prevent contamination of the 
absorbent pad by not touching it. Technicians placed the patch 
adhesive-side down in the center of the index card, recorded the 
date the patch was removed and the condition of the patch, and 
placed the card in a resealable bag. The bag was sealed and stored 
in a refrigerator until transferred to a freezer at the end of the day. 
At the conclusion of the study, patches were sent to 
PharmChem Laboratories, Inc. (Menlo Park, CA) for analysis. The 
patches were coded, randomized, and analyzed as blind speci- 
mens by the laboratory. The absorbent pad was removed from the 
adhesive layer, placed in a 5-mL screw-cap plastic tube with 2.5 
mL of a sweat extraction buffer, 75% methanol/25% 0.2M sodium 
acetate (pH 5.0), and shaken for 30 min to extract the opiates. The 
eluent was then analyzed according to package directions by com- 
petitive enzyme immunoassay (ELISA) with the STC Opiate 
Micro-Plate EIA (STC Diagnostics, Bethlehem, PA). ELISA sweat 
results were reported as nanograms per milliliter of sweat extrac- 
tion buffer according to the standardized reporting format. A 10- 
ng/mL cutoff was established and validated by STC Diagnostics 
and was used in this study. Because 2.5 mL of buffer was used to 
extract the patch, the 10-ng/mL cutoff concentration is equiva- 
lent to a concentration of 25 ng/patch. Both PharmChem 
Laboratories, Inc., which holds the license for PharmChek sweat 
patch distribution and which provides the analysis of these 
patches for treatment, criminal justice, and workplace drug- 
testing programs, and STC Diagnostics, manufacturer of the 
reagents, report results as nanograms per milliliter of elution sol- 
vent. The percent cross-reactivity at ]0 ng/mL for each analyte 
was 100% for morphine, 28% for heroin, 30% for 6-acetylmor- 
phine, 588% for codeine, 143% for hydrocodone, 16% for hydro- 
morphone, and 30% for oxymorphone (26). A subset of sweat 
specimens (389 patches) was confirmed by GC-MS analysis oper- 
ated in the selected ion monitoring mode (Hewlett-Packard 5890 
Table I. Opiate Analytes Identified by GC-MS in Positive 
Sweat Patches 
Opiate analytes 
% of Positive patches 
6-AM*, Morphine, and Codeine 
37.6% 
Heroin, 6-AM, Morphine, and Codeine 
16.1% 
Codeine 
9.5% 
Morphine and Codeine 
6.9% 
6-AM and Morphine 
6.6% 
Morphine 
5.5% 
6-AM 
4.7% 
6-AM and Codeine 
4.7% 
Heroin and 6-AM 
4.0% 
Heroin, 6-AM, and Morphine 
3.3% 
All other analyte combinations 
< 1% 
* 6-AM, 6-acetylmorphine, 
GC interfaced to a Hewlett-Packard mass selective detector, 
Hewlett-Packard, Little Falls, DE) according to the laboratory's 
standard procedures. Limit of detection was 3 ng/mL for heroin, 
6-acetylmorphine, morphine, and codeine. Limits of quantitation 
were 5 ng/mL for heroin and 3 ng/mL for 6-acetylmorphine, mor- 
phine, and codeine. Cutoff concentrations for positive specimens 
were 10 ng/mL for ELISA and 5 ng/mL for GC-MS. 
Data analysis 
Four main analyses were conducted: (1) identification and 
quantitation of opiates in sweat; (2) comparison of replicate patch 
ELISA results; (3) comparison of opiate detection in sweat by 
ELISA and GC-MS; and (4) comparison of sweat test results to 
results from different combinations of urine collection periods. 
Median and maximum concentrations of heroin, 6-acetylmor- 
phine, morphine, and codeine as determined by GC-MS were cal- 
culated for opiate-positive sweat patches. In patches positive for 
opiates by GC-MS, the percent positive for specific analytes and 
for important combinations of analytes were determined. Results 
of paired patches (abdomen and back) were compared to identify 
those with discrepant ELISA results (i.e., one positive and one 
negative). 
For comparison of GC-MS and ELISA sweat results, a patch was 
considered positive by GC-MS if heroin, 6-acetylmorphine, mor- 
phine, or codeine were detected at or above 5 ng/mL and positive 
by ELISA if results were greater than or equal to 10 ng/mL. A true 
positive (TP) was defined as positive by both ELISA and GC-MS; a 
true negative (TN) was defined as negative by both ELISA and 
GC-MS; a false positive (FP) was defined as a positive ELISA result 
and negative GC-MS result; and a false negative (FN) was defined 
as negative ELISA result and positive GC-MS result. Sensitivity of 
the assay was calculated as TP/(TP + FN). Specificity was calcu- 
lated as TN/TN + FP). Efficiency was calculated as (TP + TN)/N 
where N = the total number of analyzed patches. All ratios were 
multiplied by 100 and reported as percentages. 
The results of opiate sweat tests (ELISA) of patches worn for 7 
days were compared to the results of urine opiate immunoassay 
tests (EMIT) for four different monitoring intervals with the urine 
results as the reference method. Sensitivity, specificity and effi- 
ciency were determined as described above for four urine collec- 
tion intervals: (1) Wednesday, Friday, and Monday (WFM) urine 
collections after the Tuesday sweat patch application; (2) Monday 
before and Wednesday, Friday, and Monday (MWFM) after the 
Tuesday patch application; (3) Wednesday, Friday, Monday, and 
Wednesday (WFMW) after the Tuesday patch application; and (4) 
Monday before and Wednesday, Friday, Monday, and Wednesday 
(MWFMW) after the Tuesday patch application (Figure 1). 
Comparisons were made only for those patch specimens in which 
all urine specimens collected during the comparison intervals 
were included. Actual opiate use was assumed if any urine spec- 
imen collected during the interval tested positive for opiates by 
EMIT; if all urine specimens were negative, drug abstinence was 
assumed. Sweat was determined to be positive if at least one of the 
two paired patches was positive for opiates by ELISA (cutoff con- 
centration 10 ng/mL). In addition, 7-day ELISA sweat patch 
results were compared to EMIT urine test results from single 
weekly urine collections on the Wednesday, Friday, or Monday fol- 
lowing patch application to evaluate the differences in once or 
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Journal of Analytical Toxicology, Vol. 24, October 2000 
Monitoring Windows 
Sweat Patch 
Sweat Patch 
Application 
Urine 
Removal 
Collections 
I 
I 
I 
I 
/ 
I 
I 
I 
I 
I 
M 
T 
W 
Th 
F 
S 
S 
M 
T 
W 
WFM 
MWFM 
WFMW 
MWFMW 
Figure 1. Diagram of sweat patch and urine specimen collections. Sweat 
patch results (patch applied on Tuesdays for seven days) were compared to 
opiate urine tests of specimens collected over the four time intervals as indi- 
cated by the horizontal lines. M, Monday; W, Wednesday; F, Friday. 
Subject A 
10000] 
Opiates - ELISA 
looo4 
0 I .
.
.
.
.
.
.
.
.
.
.
.
.
.
.
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.
 
=~ 10~.~_~ 
.j/~. 
_ ~  
1000] 
6-AM - GC-MS 
c~ 10 
. . . . . . .  
 ot? 9 
1000] 
Morphine - GC-MS 
. 
loo! 
/% 
c~ 1 
.......... 
0" 
. . . . .  
e .
.
.
.
.
.
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.
 
4, 
1000] 
Codeine - GC-MS 
2 4 6 8 10 12 14 16 18 
Weeks 
thrice-weekly urine collection. For the purpose of these compar- 
isons only, urine EMIT testing for opiates was used as the reference 
method and sweat patch ELISA results were compared to the 
urine results. Therefore, a TP was assigned if at least one patch and 
one urine specimen were positive; an FP was assigned if at least 
one patch was positive, but all urine specimens were negative; a 
TN was assigned if both patches and all urine specimens were neg- 
ative; and an FN was assigned if both patches were negative and at 
least one urine specimen was positive. 
Results 
Subject B 
10000] 
Opiates - ELISA 
looo 1 
Heroin - GC-MS 
0 
.
.
.
.
.
.
.
.
.
.
.
.
.
.
 
1000] 
6-AM - GC-MS 
/ 
- 
1000 ] 
Morphine - GC-MS 
/ 
10 
_ 
1:! i -~ill 
i i i -;=il 
0 
.
.
.
.
.
.
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.
 
2 4 6 8 10 12 14 16 
Weeks 
Figure 2. Semiquantitative results of sequential sweat patches collected from individual treatment 
patients over 18 weeks. Opiate (ELISA), and GC-MS concentrations of heroin, 6-acetylmorphine, mor- 
phine, and codeine were determined in replicate sweat patches applied to the abdomen (closed sym- 
bols) and back (open symbols) for one week. Horizontal dashed lines indicate cutoff concentrations for 
positive specimens (ELISA 10 ng/mL and GC-MS 5 ng/mL). Data points are not connected where spec- 
imen results are not available. 
Analyte analysis in sweat 
A total of 925 sweat patches were collected from 44 participants 
and analyzed by ELISA; 356 (38.5%) specimens tested positive for 
opiates at concentrations _ 10 ng/mL. A subset of 
389 patches (297 screen-positive and 92 screen- 
negative patches) was analyzed by GC-MS for 
heroin, 6-acetylmorphine, morphine, and codeine. 
One or more of these opiates were detected at con- 
centrations > 5 ng/mL in 274 sweat patches. A total 
of ] 15 sweat patches were negative by GC-MS. 
Heroin was identified in 67 of 274 (24.5%) patches 
with a median concentration of 10.5 ng/mL (range 
5 to 195 ng/mL). 6-Acetylmorphine was confirmed 
in the highest number of positive patches, 212 of 
274 specimens (77.4%). The median 6-acetylmor- 
phine concentration in sweat was close to that of 
heroin at 13.6 ng/mL (range 5 to 181 ng/mL). 
Similar numbers of patches contained morphine 
and codeine, 208 and 206 patches, respectively. 
The median and range of concentrations of these 
opiates in the positive patches were 15.9 ng/mL 
(range 5 to 112 ng/mL) for morphine and 13.0 
ng/mL (range 5 to 360 ng/mL) for codeine. As 
shown in Table [, 6-acetylmorphine, morphine, 
and codeine were identified concurrently in the 
largest percentage of GC-MS-positive patches 
(37.6%); 16.1% of the positive patches contained 
all four analytes. Heroin and/or 6-acetylmorphine 
were confirmed in 78.1% of the patches, with mor- 
phine and/or codeine only in 21.9%. 
ELISA opiate results and GC-MS concentra- 
tions of heroin, 6-acetylmorphine, morphine, and 
codeine concentrations in sweat collected in 
patches applied to the abdomen and to the back 
across the course of the trial are illustrated for two 
representative patients in Figure 2. Most ELISA 
sweat tests were positive for Subject A with good 
agreement between abdomen and back patch 
results. Opiate concentrations increased during 
the later weeks of the study. However, the 
increases in opiate concentration were observed 
in patches collected during July and August and 
could be due to an increase in drug use or an 
increase in sweat secretion during the summer 
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Journal of Analytical Toxicology, Vol. 24, October 2000 
months. A good correlation (30 of 32 patches) was also noted 
between the ELISA and GC-MS results with only a single uncon- 
firmed ELISA-positive and single unconfirmed ELISA-negative 
result. Heroin was found in fewer patches than 6-acetylmorphine, 
morphine, and codeine. In most positive ELISA patches, heroin 
and/or 6-acetylmorphine were confirmed in the patch substanti- 
ating heroin rather than morphine or codeine use. Approximately 
50% of patches collected from Subject B were positive for opiates 
by ELISA with generally lower concentrations in the abdomen 
~atches as compared to the back patches. There were three 
unconfirmed ELISA-positive results (6-acetylmorphine and mor- 
phine detected but below the LOQ) and five unconfirmed negative 
results. None of the patches were positive for codeine in this sub- 
ject, with greater numbers of patches confirmed positive for 
heroin and 6-acetylmorphine than morphine. 
Comparison of paired sweat patches 
The replicability of patch testing was evaluated by comparing 
paired patches placed on the abdomen and lower back. Semi- 
quantitative ELISA results were available for 437 pairs of patches 
Table II. Comparisons of Paired Sweat Patches Applied to Abdomen and Back with Discrepant ELISA Opiate Results* 
Abdomen 
Back 
Patch 
Subject 
ELISA 
GC-MS 
ELISA 
GC-MS 
pair 
code 
Opiates * 
HER* 
6-AM 
MOR 
COD 
Opiates t 
HER 
6-AM 
MOR 
COD 
1 
A 
12.7 
0 
8.1 
16.7 
8 
9.3 
0 
8.6 
15.9 
9.9 
2 
A 
2.9 
0 
0 
0 
0 
23.8 
0 
0 
8.5 
7.9 
3 
B 
11.1 
0 
2.1 
3.1 
0 
8.5 
0 
0 
2.1 
0 
4 
B 
9.4 
4.1 
4.2 
0 
0 
32.8 
5.3 
15.3 
15.9 
3.9 
5 
B 
7.9 
0 
3.4 
0 
0 
40.0 
10.1 
42.2 
13.2 
0 
6 
B 
5.2 
0 
0 
0 
0 
20.9 
22.5 
18.3 
2.9 
0 
7 
B 
4.7 
0 
0 
0 
0 
45.7 
101 
67.8 
7.7 
0 
8 
C 
9.0 
- 
- 
21.9 
- 
- 
9 
C 
19.9 
- 
- 
6,4 
- 
- 
10 
C 
2.1 
- 
- 
- 
12.8 
- 
- 
11 
E 
7.4 
0 
3.2 
0 
4,8 
45.3 
10.2 
13.8 
0 
9.6 
12 
F 
4.9 
- 
- 
- 
12.4 
0 
1.1 
0 
4.0 
13 
H 
12.4 
- 
- 
- 
5.1 
- 
- 
14 
H 
10.4 
- 
- 
- 
9.2 
- 
- 
15 
I 
14.9 
0 
5.2 
8.1 
1.8 
2.8 
- 
- 
16 
I 
15.9 
9.7 
12.1 
0 
0 
1.8 
- 
17 
I 
62.4 
4.2 
8.1 
10.5 
5.4 
2.3 
- 
18 
N 
8.2 
0 
0 
0 
0 
10.5 
0 
0 
0 
0 
19 
N 
10.6 
- 
- 
- 
4.6 
0 
0 
0 
0 
20 
O 
7.6 
0 
0 
0 
0 
11.2 
0 
0 
6.2 
0 
21 
O 
7.7 
0 
0 
1.2 
2.8 
21.7 
0 
0 
0 
6.2 
22 
P 
14.8 
- 
- 
- 
8.0 
- 
- 
23 
R 
7.4 
0 
0 
0 
3.5 
35.3 
0 
2,3 
6.0 
7.6 
24 
U 
4.3 
- 
- 
- 
13.6 
- 
- 
- 
25 
V 
23.7 
0 
6.7 
0 
5.1 
8.1 
- 
- 
26 
V 
25.3 
0 
5.1 
0 
4.2 
5.1 
- 
- 
27 
V 
23.4 
0 
0 
0 
7.3 
6.1 
- 
- 
- 
28 
V 
33.2 
0 
0 
0 
9.0 
5.4 
- 
- 
29 
X 
11.2 
0 
3.9 
0 
0 
5.7 
- 
- 
- 
30 
Y 
29.8 
7.7 
4.4 
0 
0 
6.6 
- 
- 
- 
31 
Z 
22.9 
8.5 
7.7 
0 
0 
7.7 
- 
- 
- 
32 
BB 
7.8 
0 
0 
0 
0 
30.4 
0 
0 
0 
3 
33 
BB 
6.0 
0 
0 
0 
0 
113 
0 
5.9 
0 
15.3 
34 
BB 
8.3 
0 
0 
0 
0 
74.6 
0 
2.7 
0 
8.5 
35 
EE 
6.3 
0 
0 
0 
0 
15.9 
0 
0 
0 
4.6 
36 
EE 
7.1 
0 
0 
0 
0 
10.0 
0 
0 
0 
0 
37 
HH 
10.3 
- 
- 
- 
3.4 
- 
- 
- 
38 
HH 
19.2 
0 
0 
0 
3 
7.2 
- 
- 
- 
39 
OO 
8.5 
18.4 
57.1 
34.6 
8.2 
262 
142 
160 
48.8 
7.5 
40 
OO 
9.1 
0 
0 
10.0 
10.1 
14.0 
0 
0 
10.1 
7.9 
41 
MM 
9.0 
- 
- 
- 
10.4 
- 
- 
- 
* All values are nanograms per milliliter. All specimens were tested by ELISA. A subset was confirmed by GC-MS; these results are shown when available. Specimens not analyzed 
by GC-MS are indicated by dashes (-). 
f Morphine equivalence concentrations. 
* Abbreviations: HER, heroin; 6-AM, 6-acetylmorphine; MOR, morphine; COD, codeine. 
513 
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Journal of Analytical Toxicology, Vol. 24, October 2000 
with congruent positive or negative results in 396 pairs (90.6%) 
at the 10-ng/mL cutoff. There was no significant difference in 
ELISA opiate concentrations between sweat patches applied to 
the abdomen and to the back when using a two-tailed paired t-test 
(p = 0.230, cr = 0.05). As shown in Table II, discrepant results (one 
positive and one negative) occurred in 41 pairs (9.4%); 53.7% 
were negative in the back patch and 46.3% were negative in the 
Table III. Concordance Between ELISA and GC-MS Analyses of Sweat 
Patches for Opiate Monitoring: False Positives and False Negatives* 
Subject 
ELISA 
GC-MS 
code 
Opiates t 
HER* 
6-AM 
MOR 
COD 
abdomen patch. In more than half of the discrepant pairs (51.2%), 
the semiquantitative ELISA concentrations for the positive patch 
ranged from 10 to 20 ng/mL. In 14 (34%) of the positive patches, 
concentrations ranged from 20.1 and 40 ng/mL; four patches had 
concentrations from 40.1 to 80 ng/mL; and two positive patches 
produced results of 113 and 262 ng/mL. GC-MS analysis was per- 
formed on 51 of the 82 paired patches; 31 ELISA-positive speci- 
mens and 20 of the ELISA-negative specimens. 
GC-MS results are included in Table II where 
available. Among the 51 discrepant patches tested 
in the confirmation assay, 78.4% were confirmed 
by GC-MS; there were 23 TP, 17 TN, 8 FP, and 3 
FN results. 
False Positives 
1 
EE 
10.0 
0.0 
0.0 
0.0 
0.0 
2 
A 
10.1 
0.0 
0.0 
4.7 
4.4 
3 
N 
10.5 
0.0 
0.0 
0.0 
0.0 
4 
HH 
10.5 
0.0 
0.0 
0.0 
0.0 
5 
T 
10.9 
0.0 
0.0 
0.0 
0.0 
6 
B 
11.1 
0.0 
2.1 
3.1 
0.0 
7 
X 
11.2 
0.0 
3.9 
0.0 
0.0 
8 
X 
12.0 
0.0 
2.9 
0.0 
0.0 
9 
BB 
12.1 
0.0 
0.0 
0.0 
0.0 
10 
F 
12.4 
0.0 
1.1 
0.0 
4.0 
11 
GG 
12.4 
0.0 
0.0 
0.0 
0.0 
12 
HH 
12.4 
0.0 
3.0 
3.6 
2.3 
13 
I 
13.8 
0.0 
2.2 
3.5 
3.5 
14 
Y 
14.0 
2.2 
2.9 
3.6 
2.1 
15 
BB 
14.9 
0.0 
0.0 
0.0 
0.0 
16 
E 
14.9 
0.0 
4.4 
0.0 
0.0 
17 
EE 
15.9 
0.0 
0.0 
0.0 
4.6 
18 
U 
16.0 
0.0 
0.6 
2.1 
2.0 
] 9 
X 
16.8 
0.0 
2.8 
0.0 
L4 
20 
L 
17.0 
0.0 
4.4 
3,/ 
1.8 
21 
U 
17.~ 
0.0 
0.0 
1,1 
1.4 
22 
U 
17.8 
0,0 
1.0 
2.3 
2.1 
23 
HH 
19.2 
0.0 
0.0 
0.l) 
3.0 
24 
R 
19,4 
0.0 
3.7 
4.4 
3.9 
25 
U 
20.0 
0.0 
1.3 
1.0 
1.3 
26 
BB 
23.9 
0.0 
0.0 
0.0 
0.0 
27 
U 
28.1 
0.0 
1.0 
1.5 
1.4 
28 
BB 
30.4 
0.0 
0,0 
0.0 
3.0 
29 
B 
43.3 
0.0 
0.0 
0.0 
0.0 
30 
U 
48.2 
0.0 
1.7 
2.0 
1.8 
31 
U 
74.6 
0.0 
2.5 
4.0 
2.3 
32 
U 
89.5 
0.0 
1.5 
3.7 
3.7 
False Negatives 
1 
B 
4.2 
5.4 
4.7 
0.0 
0.0 
2 
B 
7.9 
5.2 
6.3 
0.0 
0.0 
3 
B 
8.4 
3.1 
6.8 
0.0 
0.0 
4 
OO 
8.5 
18.4 
57.1 
34.6 
8.2 
5 
B 
8.8 
0.0 
3.1 
6.4 
0.0 
6 
B 
9.0 
0.0 
5.4 
3.0 
0.0 
7 
OO 
9.1 
0.0 
0.0 
10.0 
10.1 
8 
A 
9.3 
0.0 
8.6 
15.9 
9.9 
9 
X 
9.9 
0.0 
0.0 
5.0 
0.0 
* All values are nanograms per milliliter. 
Morphine equivalents. 
* Abbreviations: HER, heroin; 6-AM, 6-aeetylmorphine; MOR, morphine: COD, codeine. 
Comparison of ELISA and GC-MS sweat results 
The presence of opiates was determined by both 
ELISA and GC-MS in 389 sweat patch specimens. 
A total of 297 (76.3%) of the 389 specimens 
screened positive by ELISA (> 10 ng/mL cutoff); of 
these, 265 (89.2%) were confirmed positive by 
GC-MS (_> 5 ng/mL) for heroin, 6-acetylmor- 
phine, morphine, and/or codeine. A similar rate of 
confirmation (90.2%) was achieved for the 92 
screen-negative sweat specimens when analyzed 
by GC-MS. In the entire sample set, 265 were 
identified as TP (ELISA and GC-MS positive), 83 
as TN (ELISA and GC-MS negative), 32 as FP 
(ELISA positive and GC-MS negative), and 9 as FN 
(ELISA negative and GC-MS positive) test results. 
FN specimens may be under-represented because 
of the small number of ELISA-negative specimens 
that were confirmed by GC-MS. The overall corre- 
lation (i.e., efficiency) of ELISA and GC-MS test 
results was 89.5%, with 96.7% sensitivity and 
72.2% specificity. 
ELISA sweat results for FP and FN specimens 
and respective GC-MS data are presented in Table 
III. Of the 32 FP tests, 25 had ELISA results < 20 
ng/mL or close to the assay cutoff. One or more of 
the four opiate analytes were identified in 20 of 
these specimens by GC-MS, albeit below the > 5- 
ng/mL cutoff. The number of FN results by 
GC-MS was low (N = 9), although a much smaller 
percentage of screen-negative specimens were 
analyzed. In all but two of the FN tests, the ELISA 
results were less than 20% below the cutoff of 10 
ng/mL. In five of the FN patches, the total concen- 
tration of opiate analytes as determined by GC-MS 
was < 10 ng/mL. 
Detection of opiate use by sweat and 
urine testing 
Figure 3 illustrates six representative patients' 
patterns of opiate concentrations in sweat patches 
applied for one-week periods to the abdomen and 
back and qualitative urine results (positive or neg- 
ative at 300 ng/mL) obtained from specimens col- 
lected three times weekly across the course of the 
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Journal of Analytical Toxicology, Vol. 24, October 2000 
trial. Dashed lines indicate the 10-ng/mL cutoff concentration for 
the ELISA analysis in sweat. Semiquantitative opiate concentra- 
tions by ELISA are included for comparison. Urine EMIT results 
are either negative (< 300 ng/mL) or positive (> 300 ng/mL). 
Subject C had only a few positive opiate sweat and urine test 
results, primarily at the beginning of the treatment program. 
Opiate use declined significantly from days 12 through 51. 
Subject D had a similar pattern of results with consistent nega- 
tive sweat and urine opiate tests from days 25 through 51, indi- 
cating decreased heroin use. Almost all sweat patches and most 
urine test results were positive for Subject E reflecting continued 
heroin use. Urine and sweat results for Subject F were concor- 
dant in almost all cases; the subject appeared to abstain from 
heroin use throughout most of the study with occasional heroin 
use documented in both urine and sweat test results. This partic- 
ipant had one sweat patch positive for opiates that was not 
accompanied by a positive urine specimen. Subject G is an inter- 
esting case with 23 positive urine tests throughout the study with 
no positive sweat patches. Subject H also had a large number of 
negative sweat patches with frequent single positive urine tests 
interspersed between negative urine results. Negative sweat 
patches with positive urine tests over the corresponding times 
occurred in only 13 of 44 subjects. Of these 13 subjects, 8 had 
only 1 or 2 negative sweat results. Three subjects had 7, 9, and 13 
negative sweat patch results when a urine test was positive. A 
similar number of subjects (15 of 44) had positive sweat patches 
collected during weeks when all corresponding urine tests were 
negative. The majority (12 of 15) had only 1 or 2 inconsistent 
sweat and urine results; however, one individual had six positive 
sweat patch tests when the urine specimens were negative for 
opiates. 
The relationship between urine and sweat drug tests was eval- 
uated by comparing ELISA sweat results (10-ng/mL cutoff) from 
355 patch pairs to EMIT results of urine specimens collected over 
four different time periods: WFM, WFMW, MWFM, and MWFMW 
(see Figure 1 for timeline). Concordance between sweat and 
urine was consistent across all four urine collection intervals 
(Table III), with sensitivity ranging from 63.4 to 68.6%, specificity 
1100~ ] ~ 
Subject C 
Po~ 
N~ 
0 3 6 9 1215182124273033363942454851 
1000" ~ 
100" 
~ 
10"- 
c 
1 
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
 
0 3 6 9 1215182124273033363942454851 
1000" 
Subject F 
100" 
10" 
1 
N~ . . . . . . . . . . . . . . . . . .  
0 3 6 9 121518212427303336394245485154 
10 
..... 
Neg 
0 3 6 912151821242730333639424548 
10000" 
.J I000" 
I00" 
c 
I0" 
1" 
Sublect S 
looo 
~
r
 
100" 
10' 
1 
0 3 6 9 12 15 18 21 24 27 30 33 36 39 
Study Day 
Subject H 
0 3 6 91215182124273033363942454851 
Study Day 
Figure 3. Semiquantitative results of sequential sweat patch (top panels) and urine specimens (bottom panels) collected from selected treatment patients over 18 weeks. 
Opiate (ELISA 300-ng/mL cutoffl concentrations were determined in replicate sweat patches applied to the abdomen (closed symbols) and back (open symbols) for one 
week. Horizontal dashed lines indicate cutoff concentrations for positive specimens (10 ng/mL for sweat patches). Qualitative opiate EMIT results (closed triangle sym- 
bols lower panel) were determined in urine specimens collected Mondays, Wednesdays, and Fridays. Data points are not connected where specimen results are not 
available. 
515 
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Journal of Analytical Toxicology, Vol. 24, October 2000 
ranging from 86.1 to 87.8%, and efficiency ranging from 75.8 to 
78.6% at the 10-ng/mL ELISA cutoff. Concordance was reduced 
when a 5 ng/mL ELISA cutoffwas applied: 33.0% TP; 37.5% TN; 
19.4% FP; 10.1% FN; 76.5% sensitivity; 65.8% specificity; and 
70.4% efficiency for the WFM urine collection interval. 
Table IV. Mean Percent Concordance of Detection of Opiate Use in 
Sweat and Urine from 44 Participants* 
WMF 
MWFM 
WFMW 
At least one urine specimen tested positive for opiates by EMIT 
at 300 ng/mL in 153 out of 355 sets of WFM urine specimens. This 
frequency of positives was higher than that found in the corre- 
sponding sweat patch specimens, in which 134 of 355 patch pairs 
were found to have ELISA opiate concentrations above 10 ng/mL. 
When ELISA sweat results were compared to 
EMIT urine results (reference method for this 
comparison), 29.6% TP, 49.0% TN, 7.9% FP, and 
13.5% FN were found for the WFM urine compar- 
MWFMW 
ison. As shown in Table IV, there were 28 cases that 
had a result > 10 ng/mL in at least one of the 
63.4% 
87.8% 
ELISA sweat patches when the EMIT results were 
75.8% 
less than 300 ng/mL for all three urine specimens. 
31.3% 
Additional information was obtained to evaluate 
6.2% 
these 28 cases. In all but one case, duplicate sweat 
18.0% 
patches were analyzed by ELISA. In 15 of the 27 
44.5% 
sweat patch pairs, the ELISA opiate concentration 
was < 10 ng/mL in one of the patches. GC-MS 
analyses are included in Table V for 29 of the 40 FP 
sweat patches. Twenty-three of the ELISA results 
were confirmed positive for heroin, 6-acetylmor- 
phine, morphine, and/or codeine; 6 positive 
Sensitivity 
68.6% 
64.7% 
65.8% 
Specificity 
86.1% 
87.6% 
86.1% 
Efficiency 
78.6% 
76.6% 
76.9% 
True Positive* 
29.6% 
31.0% 
29.9% 
False Positive 
7.9% 
6.5% 
7.6% 
False Negative 
13.5% 
16.9% 
15.5% 
True Negative 
49.0% 
45.6% 
47.0% 
* Sweat specimens were analyzed by ELISA (lO-ng/mL cutoff); urine specimens were analyzed by EMIT 
(300-ng/mL cutoff). 
True Positive, at least one patch and one urine specimen were positive; false positive, at least one patch was 
positive and all urine specimens were negative; false negative, if both patches were negative and at least one 
urine specimen was positive; true negative, both patches and all urine specimens were negative. 
Table V. ELISA Opiate Concentrations In Positive Sweat Patches from Subjects with Opiate-Negative Urine* 
Subject 
ELISA 
GC-MS 
ELISA 
GC-MS 
code 
Opiates ~ 
HER s 
6-AM 
MOR 
COD 
Opiates t 
HER 
6-AM 
MOR 
COD 
Specimen 
1 
B 
98.1 
94.4 
70.7 
13.9 
0.0 
18.4 
17.7 
13.2 
2.8 
0.0 
2 
B 
19.4 
17.7 
12.0 
4.3 
0.0 
11.8 
8.4 
5.8 
0.0 
0.0 
3 
B 
40.0 
10.1 
42.2 
13.2 
0.0 
7.9 
0.0 
3.4 
0.0 
0.0 
4 
B 
20.9 
22.5 
18.3 
2.9 
0.0 
5.2 
0.0 
0.0 
0.0 
0.0 
5 
B 
12.7 
6.3 
6.6 
0.0 
0.0 
21.3 
0.0 
19.3 
4.7 
0.0 
6 
B 
45.7 
101.0 
67.8 
7.7 
0.0 
4.7 
0.0 
0.0 
0.0 
0.0 
7 
C 
25.8 
- 
70.6 
- 
- 
- 
8 
C 
6.4 
- 
19.9 
.
.
.
.
 
9 
C 
12.8 
- 
2.1 
- 
- 
- 
10 
F 
81.9 
0.0 
0.0 
0.0 
21.3 
78.0 
0.0 
0.0 
0.0 
17.9 
11 
F 
16.1 
0.0 
0.0 
2.1 
6.6 
18.9 
0.0 
0.0 
0.0 
5.9 
12 
I 
2.8 
- 
14.9 
5.2 
8.1 
1.8 
1.8 
13 
I 
1.8 
- 
15.9 
9.7 
12.1 
4.2 
1.0 
14 
N 
10.5 
0.0 
0.0 
0.0 
0.0 
8.2 
0.0 
0.0 
0.0 
0.0 
15 
N 
4.6 
0.0 
0.0 
0.0 
0.0 
10.6 
.
.
.
.
 
16 
O 
11.2 
- 
- 
- 
7.6 
.
.
.
.
 
17 
P 
8.0 
- 
- 
14.8 
.
.
.
.
 
18 
P 
47.7 
- 
94.5 
.
.
.
.
 
19 
T 
18.2 
.
.
.
.
.
.
.
.
 
20 
U 
27.2 
- 
- 
- 
89.5 
0.0 
1.5 
3.7 
3.7 
21 
X 
5.7 
- 
- 
- 
11.2 
0.0 
3.9 
0.0 
0.0 
22 
AA 
191.3 
0.0 
13.6 
9.5 
16.9 
125.5 
0.0 
7.2 
7.2 
12.9 
23 
BB 
23.9 
0.0 
1.7 
0.0 
0.0 
14.9 
26.8 
51.6 
0.0 
0.0 
24 
EE 
10.0 
0.0 
0.0 
0.0 
0.0 
7.1 
0.0 
0.0 
0.0 
0.0 
25 
EE 
17.8 
0.0 
6.3 
0.0 
0.0 
13.2 
0.0 
10.9 
0.0 
0.0 
26 
EE 
75.2 
53.6 
34.8 
8.1 
0.0 
57.3 
33.9 
34.4 
6.9 
0.0 
27 
HH 
7.2 
- 
- 
- 
19.2 
0.0 
0.0 
0.0 
3.0 
28 
OO 
14.0 
0.0 
0.0 
10.1 
7.9 
9.1 
0.0 
0.0 
10.0 
10.1 
* All values are nanograms per milliliter. All specimens tested by ELISA; a subset was confirmed by GC-MS; these results are shown where available. Specmlens no1 analyzed by 
GC-MS are indicated by dashes (). 
Morphine equivalents. 
* Abbreviations: HER, heroin; 6-AM, 6-acetylmorphine; MOR, morphine: COD, codeine. 
516 
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Journal of Analytical Toxicology, Vol. 24, October 2000 
ELISA results were not confirmed by GC-MS. Seven discrepant 
patches that tested negative in the screening assay were also 
tested by GC-MS; six were confirmed as negative and one was 
confirmed as a FN specimen. 
Not all treatment, criminal justice, or workplace testing pro- 
grams collect three urine specimens each week for drug moni- 
toring. Therefore, we also compared ELISA sweat patch results to 
single urine specimens collected the Wednesday, Friday, or 
Monday following patch application. The sensitivity, specificity, 
efficiency, TP, FP, TN, and FN percentages of these comparisons 
are included in Table VI. The number of false negative sweat 
results decreased significantly, resulting in a substantial increase 
in sensitivity to greater than 90% as compared to urine testing. 
However, greater numbers of false-positive sweat results 
decreased specificity from 86% when compared to the thrice- 
weekly urine collections to approximately 75% when sweat was 
compared to the single Wednesday, Friday, or Monday urine col- 
lection. Overall, the efficiency of opiate sweat testing as compared 
to urine opiate testing remained about 78%. 
Discussion 
Drug testing of biological matrices is an effective tool for the 
diagnosis of drug exposure; for the assessment of drug absti- 
nence; and for deterrence of drug use in treatment, workplace, 
military, and criminal justice programs. No single analytical tech- 
nique or single biological matrix can be expected to fulfill the 
needs and resolve the diverse issues posed by the goals of the dif- 
ferent drug-monitoring programs. Additional methods for moni- 
toring drug use are needed. This study is part of an ongoing 
program to develop improved biological monitoring procedures. 
In the present study, we compared sweat testing (ELISA and 
GC-MS) to urine testing (EMIT) for monitoring opiate use. 
Heroin, 6-acetylmorphine, morphine, and codeine were mea- 
sured by GC-MS in sweat collected from outpatient treatment 
patients. 6-Acetylmorphine, morphine, and codeine were detected 
concurrently in approximately 75% of all positive patches, with 
heroin identified in approximately 25% of positive patches. Thus 
Table Vl. Mean Percent Concordance of Detection of 
Opiate Use in Sweat and Urine from 44 Participants* 
W t 
F 
M 
Sensitivity 
95.1% 
93.7% 
90.9% 
Specificity 
75.9% 
74,8% 
75.7% 
Efficiency 
76.7% 
77.4% 
78.3% 
True Positive* 
21.1% 
22.0% 
22.3% 
False Positive 
16.9% 
15.8% 
15.5% 
False Negative 
6.8% 
6.2% 
8.2% 
True Negative 
55.2% 
56.1% 
54.1% 
* Sweat specimens were analyzed by ELISA (10-ng/mL cutoff); urine specimens 
were analyzed by EMIT (300-ng/mL cutoff). 
* Single weekly sweat patch compared to single urine specimen collected on 
Wednesday, Friday, or Monday following sweat patch application. 
* True Positive, patch and urine results were positive; false positive, positive patch, 
and negative urine results; false negative, negative patch, and positive urine 
results; true negative, patch and urine results were negative. 
it appears that sweat testing for opiates is frequently useful for con- 
firming heroin use as the source of the opiate positive rather than 
another form of opiate exposure. In the present study, the identifi- 
cation of heroin and/or 6-acetylmorphine in 78.1% of positive 
sweat patches identified heroin use, rather than licit codeine or 
morphine or the ingestion of food containing small concentra- 
tions of opiates. Confirmation of 6-acetylmorphine in urine also 
confirms heroin use; however, the short detection time of this ana- 
lyte in urine is an important limiting factor. In controlled low-dose 
heroin-administration studies, 6-acetylmorphine was detected in 
urine only 2-4 h after 3 and 6 mg heroin administration (27). The 
patch may provide a longer window of detection, up to a week or 
more, after heroin administration because 6-acetylmorphine is 
collected and stored in the patch. 
The sweat patch may be less susceptible than urine to the pro- 
duction of positive test results due to the consumption of poppy 
seed containing foods (28-36). Fogerson et al. (26) reported that 
all sweat patches tested negative for opiates by ELISA (10-ng/mL 
cutoff) and GC-MS (5-ng/mL cutoff) following ingestion of up to 
30 g of poppy seeds in bakery products. In contrast, urine speci- 
mens collected during the same time frame were positive (EMIT 
300-ng/mL cutoff) on the first day after consuming three poppy 
seed bagels. Recently, the cutoff concentration for opiates in the 
federally mandated urine drug testing program was raised to 
2000 ng/mL, in part because of the production of positive urine 
results from poppy-seed ingestion. 
The results of the present study are generally consistent with 
other laboratory studies of opiate secretion in sweat. In the cur- 
rent study, median heroin, 6-acetylmorphine, morphine, and 
codeine concentrations in positive patches were 10.5, 13.6, 15.9, 
and 13.0 ng/mL, respectively. In a controlled intravenous admin- 
istration of 20 mg heroin to two participants, maximum heroin 
concentrations of 48.7 and 53.3 ng/patch (equivalent to 19.5 and 
21.3 ng/mL) were measured in the first 24 h patch (13). Heroin 
concentrations were decreased with stable or increasing 6-acetyl- 
morphine concentrations in patches worn for five days compared 
to patches worn for shorter periods. Morphine was not detected in 
any patch. Heroin and 6-acetylmorphine sweat concentrations 
measured in the present study are consistent with those reported 
in the controlled dosing study; however, morphine and codeine 
were routinely identified in the positive sweat specimens col- 
lected from treatment patients. Codeine and morphine are fre- 
quent contaminants in illicit heroin and would not have been 
present in the pharmaceutical-grade heroin administered in the 
controlled study. The origin of the morphine identified in our 
positive sweat patches could have been from the metabolism of 
heroin and/or codeine and morphine in the illicit drug prepara- 
tion or possibly from the breakdown of heroin or 6-acetylmor- 
phine collected in the patch. In another laboratory study, the 
secretion of codeine in sweat over 24 h was measured following 
oral administration of 60 mg of codeine to six subjects (23). 
Codeine was detectable in the patch within 1 h; peak concentra- 
tions of 17 to 124 ng/patch occurred from 4 to 24 h after drug 
administration. If the 5-ng/mL GC-MS cutoff used in the present 
study had been used, 4 of the 24 patches would have been nega- 
tive for codeine. In another codeine dosing study, analysis of 
sweat patches for codeine and morphine by GC-MS following oral 
administration of 30- and 60-rag doses of codeine were found to 
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reliably reflect codeine exposure (concentration data were not 
provided) (26). However, when 10 mg oral heroin or 13.9 mg of 
smoked heroin was administered in the same study, no sweat 
patches were positive for heroin, 6-acetylmorphine, or morphine. 
The authors (26) suggested that the minimum detectable dose of 
heroin was 20 mg by the intravenous route. 
Reports of heroin, 6-acetylmorphine, morphine, and codeine 
concentrations in sweat collected in other treatment studies were 
also consistent with the results reported in this investigation. In a 
study of 17 heroin users who wore sweat patches for 3 to 7 days 
during outpatient drug treatment, heroin concentrations ranged 
from 0 to 400 ng/patch, 6-acetylmorphine concentrations ranged 
from 0 to 441 ng/patch, and morphine concentrations ranged 
from 0 to 156 ng/patch (13). Heroin concentrations exceeded 
6-acetylmorphine concentrations in approximately half the 
patches; morphine concentrations were generally equivalent to 
or less than 6-acetylmorphine concentrations. In another study of 
20 drug-treatment patients, heroin use was attributed to 8 
patients and codeine use to 4 patients based on GC-MS analytical 
results from sweat patches worn for five days (7). Heroin, 6- 
acetylmorphine, and morphine concentrations ranged from 37 to 
175 ng/patch, 60 to 2386 ng/patch, and 29 to 271 ng/patch, 
respectively, in the heroin abusers. The 6-acetylmorphine con- 
centration always exceeded the heroin and usually the morphine 
concentration in the same patch. In the four codeine users, the 
morphine concentration was generally 10% or less of the parent 
drug concentration in sweat. Codeine concentrations ranged 
from 67 to 4018 ng/patch. 6-Acetylmorphine (up to 200 ng/patch) 
was the primary analyte detected in the sweat of two heroin 
abusers enrolled in a drug rehabilitation clinic. Lower concentra- 
tions of morphine (up to 50 ng/patch) and codeine (up to 25 
ng/patch) were identified: however, heroin was not detected (24). 
In a single case study, sweat test results from one drug addict were 
reported as 234 ng/patch heroin, 1587 ng/patch 6-acetylmor- 
phine, 59 ng/patch morphine, and 73 ng/patch codeine (21). The 
patch was also positive for desmethyldiazepam, oxazepam, and 
tetrahydrocannabinol. 
Cocaine concentrations measured in the same sweat patches 
have been previously reported (19). In the positive sweat patches, 
median and maximum cocaine concentrations were found to be 
378 and 26,490 ng/mL, respectively. Cocaine concentrations far 
exceeded opiate concentrations, and although the amounts of 
self-administered cocaine and opiate doses were unknown, these 
results are consistent with the finding of significantly greater 
concentrations of cocaine in sweat and hair, as compared to opiate 
concentrations in these alternative matrices. 
Duplicate patches were applied to subjects in the current study 
to assess replicability of results from different regions of the body. 
The replicability of duplicate patches applied to the abdomen and 
lower back was high in the present study, with greater than 90% 
concordance. Although discrepant results (one positive and one 
negative) occurred in 9.4% of 437 pairs analyzed by ELISA, half of 
the discrepancies occurred in specimens with opiate concentra- 
tions (ELISA) close to the 10 ng/mL cutoff concentration. GC-MS 
confirmation of the two highest concentration discrepant patch 
results (pairs 34 and 39 in Table II) confirmed the presence of sig- 
nificant levels of opiates in the patches. In one case (pair 39), the 
positive and negative patches were found to be positive by 
518 
Journal of Analytical Toxicology, Vol. 24, October 2000 
GC-MS, and in the other case, only the positive patch was found 
to be positive. In addition, these opiate concentrations were well 
within the ranges documented in other published reports of 
opiate concentrations in sweat, reducing the probability of con- 
tamination of the patch. The high replicability of the patch pairs 
suggests that the placement of patches does not significantly 
affect the outcome and thus supports the utility of the procedure 
for monitoring drug use. 
GC-M$ confirmation of ELISA sweat results was 89.5% (348 of 
389) with 10.8% unconfirmed-positive-screening results (32 of 
297) and 9.8% unconfirmed-negative-screening results (9 of 92). 
Thus, the ELISA assay with a 10-ng/mL cutoff concentration 
appears to be a sensitive and specific screening assay for detecting 
opiates in sweat patches. 
Because patches were applied on Tuesdays and urine specimens 
were collected on a Wednesday-Friday-Monday schedule, and 
given that opiates reside in the body for several days, it was 
unclear which set of urine specimens should be compared to the 
patch data. Drug taken after the Monday urine specimen and 
before patch removal on Tuesday could be detectable in the patch. 
Comparison of sweat patch results to four different urine collec- 
tion intervals produced approximate mean sensitivities, specifici- 
ties, and efficiencies of 65%, 86%, and 77%, respectively, for all 
four sets of results (Table IV). Overall, sweat patches applied on 
Tuesday and removed the following Tuesday adequately reflected 
opiate use detected in the urine specimens collected on the 
Wednesday, Friday, and Monday while the patches were worn. 
More opiate use was detected by thrice-weekly urine testing than 
by duplicate sweat patch testing in this comparison. However, the 
majority of sweat patches found positive for opiates by ELISA in 
the absence of opiate positive urine were confirmed positive by 
GC-MS. This suggests that these patch results were true posi- 
tives. Increased detection of opiate use with thrice-weekly urine 
testing may be due to higher drug concentrations in urine: col- 
lection of a small total amount of sweat and hence, low total 
amounts of drug in the patch; and/or higher cross-reactivity of 
the EMIT assay with the primary analyte found in urine as com- 
pared to the lower cross-reactivity of ELISA with 6-acetylmor- 
phine, the primary analyte in sweat; and/or differences in 
analytical cutoffs. Sweat and urine opiate results agreed better 
using the 10-ng/mL ELISA cutoff concentration than using the 
lower 5-ng/mL sweat cutoff. Thus, lowering the screening cutoff 
concentration did not result in an improved correlation between 
the two methods. 
Three other comparisons of sweat and urine monitoring of 
opiate use have been reported in the recent literature. Interpatch 
reliability and validity of patch results in comparison to urine 
tests collected at the beginning and end of patch application were 
evaluated in methadone-maintenance patients (37). Patches were 
worn for 5 to 10 days and were analyzed with an opiate im- 
munoassay (Cozart Bioscience Ltd., Abingdon, U.K.; cutoff 7.5 
ng/patch). Urine specimens were tested for opiates by EMIT 
immunoassay with a cutoff of 300 ng/mL. Duplicate patches worn 
on the side and arm had similar qualitative results for opiates in 
96% of the patches. There was 100% agreement between the 
sweat and urine results with 28 positive and 3 negative test 
results. Patches were well tolerated by participants, although 
some patients reported minor skin irritation. There was no 
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Journal of Analytical Toxicology, Vol. 24, October 2000 
evidence of reduction of illicit drug use during periods of sweat 
patch monitoring. The authors concluded that sweat patches 
were a reliable, albeit more expensive, means of monitoring drug 
use in the methadone-maintenance clinic. 
A large study evaluating 2885 sweat patches and 10,080 urine 
specimens collected from 1054 subjects compared the efficiency 
of detection of opiate use by sweat and urine monitoring in a 
criminal justice population (38). Two distinct subject populations 
were studied. In a three-month comparison of sweat and urine 
monitoring of opiate use in subjects in the residential and elec- 
tronic monitoring sites of the Michigan State Department of 
Correction Facilities, urine specimens were collected every three 
days and sweat patches were worn for 7 to 14 days. In a second 
component of the study conducted over six months with prison 
inmates, urine specimens were collected at the time of sweat 
patch application and at removal 7 to 14 days later. Urine speci- 
mens were screened for opiates by EMIT at 300 ng/mL and con- 
firmed by GC-MS (cutoff not described). Sweat patches were 
analyzed for opiates with the same STC immunoassay as used in 
the present study with a 10 ng/mL cutoff and were confirmed by 
GC-MS (10 ng/mL). In this study, the percentages of total sweat 
patches and urine specimens found to be positive for opiates over 
the course of the study were compared to evaluate the efficiency 
of drug detection by sweat and urine testing. One percent of the 
total patches were positive for opiates as compared to 0.3% of the 
urine specimens. These data indicate that a single sweat patch 
worn for 7 to 14 days detects more opiate use than a single urine 
specimen collected during the time the patch is worn. In order to 
compare the results from the present study with these data, a sim- 
ilar comparison of total urine specimens to total sweat patch 
results was made. In our study population of methadone-mainte- 
nance treatment patients, 31.6% of the total number of urine 
specimens were found to be positive for opiates as compared to 
37.7% of the total number of sweat patches collected over a four- 
month period. 
The results of a pilot program of the Administrative Office of the 
U.S. Courts was presented at the Substance Abuse and Mental 
Health Services Administration meeting on the use of alternative 
matrices for drug testing. This program was designed to deter- 
mine the usefulness of sweat patches for monitoring drug use in 
the Federal probation program. Sweat patches were applied for 
7 to 14 days with urine collection at the time of patch application 
and removal. A total of 396 subjects provided 875 sweat patches 
and 782 urine specimens. ELISA screening and GC-MS confir- 
mation of sweat patch results utilized a 10-ng/mL cutoff. EMIT 
screening and GC-MS confirmation of urine results used cutoffs 
of 300 ng/mL and 150 ng/mL, respectively. In this population, 
0.5% (4 of 782) of the total sweat patches tested positive for opi- 
ates as compared to 1.4% (11 of 782) of the two urine specimens 
collected during/close to the time of sweat patch wear. It was 
interesting to note that almost all of the positive opiate tests indi- 
cated use of codeine rather than heroin. The authors concluded 
that in this population, urine testing was more sensitive than 
sweat testing for the detection of opiate use. 
The concordance of sweat and urine tests in the detection of 
drug use is greatly affected by the cutoff concentrations of the 
immunoassay tests and by the frequency of urine collection. At 
the time this study was being conducted, the federally mandated 
immunoassay cutoff concentration for workplace monitoring of 
opiates was 300 ng/mL. Since this time, the federally mandated 
opiate cutoff concentration has been raised to 2000 ng/mL. It is 
expected that treatment drug testing programs will continue use 
of the 300-ng/mL cutoff concentration for opiates. However, in a 
comparison of sweat and urine testing in programs using the 
2000-ng/mL urine cutoff, it would be expected that sweat testing 
would identify more cases of opiate exposure because of its much 
lower cutoff. In addition, the present study compared a weekly 
sweat patch with three weekly urine specimens. When we com- 
pared the sweat patch opiate results to urine specimens collected 
once a week on the Wednesday, Friday, or Monday after patch 
application, the number of false-negative patch results decreased 
and the number of false*positive results increased, with resultant 
increases in sensitivity and decreases in specificity. Therefore, if 
the frequency of urine collection is reduced to one urine spec- 
imen per week, sweat testing identified the same or slightly more 
opiate use as compared to urine testing. 
Few problems were encountered in using the patches in the 
outpatient population. In one patient, patches did not reliably 
adhere over a seven-day period and participation in the study was 
terminated. This individual was moderately obese and worked in 
a position that required repetitive motion that caused rubbing of 
the patch against his clothing. With a second person, an allergic 
reaction developed at the site of the patch. The rash appeared to 
be due to the use of alcohol on the skin for cleansing; the rash 
resolved completely when the patch use was discontinued. 
Potentially more problematic is the possible external contami- 
nation of patches during application to the skin and during the 
removal process. The rate of discrepant results of duplicate sweat 
patches was low in this study, indicating little problem with 
external contamination. Care was taken to ensure that patches 
were handled properly according to manufacturer's directions. 
False-positive sweat patches (compared to urine) were usually 
associated with low opiate sweat concentrations, suggesting a 
threshold phenomenon rather than environmental contamina- 
tion. A recent report on the persistence of externally applied 1 IJg 
alcoholic solutions of cocaine and tetrahydrocannabinol to the 
skin indicated that these drugs or metabolites may remain 
detectable for up to three days (39). Normal hygiene did not 
remove the drug. The authors suggest that cleaning of the skin 
with isopropanol, as required prior to patch application, may be 
insufficient to remove residual drug. This is the only report 
describing this phenomenon; further research is needed to 
resolve this important issue. 
Advantages of sweat testing over urine testing include a wider 
drug detection window, easier specimen collection, reduced oppor- 
tunity for adulteration, and the ability to more frequently differen- 
tiate illicit heroin use from licit codeine and opiate-containing food 
ingestion. Disadvantages of sweat testing include the lack of 
automation of sweat patch analysis, increased cost, minimal con- 
trolled drug administration data to interpret sweat test results, 
especially for drugs other than cocaine, and a qualitative rather 
than quantitative profile of drug use. It may be possible in the 
future to compare drug concentrations in sweat to a marker in 
sweat, such as lactic acid, thereby removing the effects of variable 
diaphoretic volume. Additional research is needed to determine if 
this is a feasible approach to obtaining more quantitative drug use 
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information. This would be analogous to the normalization of drug 
concentrations in urine to the urine creatinine concentration. 
In summary, sweat testing provides a useful alternative for 
monitoring opiate usage. The patches were easy to apply and 
adhered appropriately to most participants. Heroin, 6-acetylmor- 
phine, morphine, and codeine in sweat detected by ELISA at a 10- 
ng/mL cutoff concentration was reliably confirmed by GC-MS at 
a 5-ng/mL cutoff concentration. Finally, there was good corre- 
spondence in detection of opiate use between thrice-weekly urine 
monitoring and weekly sweat patch monitoring. 
Acknowledgment 
The Intramural Research Program of the National Institute on 
Drug Abuse supported this study. PharmChem Laboratories, Inc. 
(Menlo, CA) provided analyses of sweat patches. We are grateful to 
Drs. Kenneth Silverman and Charles R. Schuster who helped 
design the clinical trial and Rebecca Sneeringer for technical 
assistance. 
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