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Does naloxone cause a positive urine opiate screen?
BRIEF REPORT
D o e s Naloxone Cause a Positive Urine Opiate Screen? From the Departments of Emergency Medicine* and Pathology, t Wilford Hall Medical Center, San Antonio, Texas. Received for publication January 21, 1994. Revision received April 2 7, 1994. Accepted for publication May 6, 1994.
Alan B Storrow, MD*
Study objective: Todetermine whether the excreted metabo-
Frank H Wians, Jr, PhD, MT
lites of naloxone hydrochloride cause positive urine toxicologic screens for opiates.
(ASCP), DABCCt Stephen L Mikkelsen, MS, MT (ASCPp John Norton, BA, MT (ASCP)t
Presented at the American College of Emergency Physicians Research Forum, San Diego, California, March 1994; and at the Tri-Service Symposium in Emergency Medicine, San Antonio, Texas, April 1993. The opinions or assertions contained herein are those of the authors and should not be construed as official or as representing the opinions of the Department of the Air Force, Department of the Army, or the Department of Defense. Copyright 9 by the American College of Emergency Physicians.
Design: Prospective, randomized, double-blinded human protocol.
Setting: Urban Level I military emergency department. Participants: Fourteen adult volunteers who took no routine medications, were not pregnant, had no known sensitivity to
naloxone,and who were negative for a pretest urine and serum toxicologic screen. Interventions: We administered either 2 or 4 mg IV naloxone to 14 subjects. Urine drug screening was obtained before administration and at 60 minutes, 6 hours, and 48 hours after administration. Results: All urine drug screens using the enzyme-multiplied immunoassay technique were negative for opiates at both dosage levels. The sample size of 14 yielded a power of more than .99 to detect the difference between positive and negative samples. Conclusion: Although the metabolites of naloxone hydrochloride are similar in structure to oxymorphone and are excreted in human urine for several days, naloxone was not associated with a positive enzymatic urine screen for opiates. [Storrow AB, Wians FH Jr, Mikkelsen SL, Norton J: Does naloxone cause a positive urine opiate screen? Ann EmergMed December 1994;24:1151-1153.]
DECEMBER 1994 24:6 ANNALS OF EMERGENCYMEDICINE
1151
NALOXONE Storrow et al
i
INTRODUCTION
Naloxone hydrochloride has found widespread use for its opiate antagonist activity and excellent safety profile. It is given routinely to patients with acute alterations in mental status or with suspected opiate toxicity It is a synthetic congener of oxymorphone because of the replacement of a methyl group for an allyl group (Figure). 1 Naloxone is conjugated, dealkylated, and reduced in the liver to three compounds. 2 It requires up to 72 hours to be 70% eliminated by the kidney 3 Despite the structural similarity to opiates and the common use of urine drug screening (UDS) after naloxone administration, the effect of naloxone on UDS has not been reported. Furthermore, the use of UDS in the military and corporate sector makes the implication of a faulty result all the more grave. We conducted a study to determine the effect of IV naloxone use on urine opiate screening. MATERIALS AND METHODS
Our study protocol was approved by the Wilford Hall Medical Center Institutional Review Committee. Fourteen healthy, adult volunteers aged 18 to 55 years (mean, 29.1 years; SD, 3.1 years) underwent the administration of either 2 or 4 mg IV naloxone. Exclusion criteria included the ingestion of any medication within 72 hours before the study; a positive urine or serum drug screen; pregnancy; or underlying pulmonary, cardiac, renal, neurologic, or psychiatric disease. Each volunteer underwent the placement of an IV heparin lock after initial urine and serum samples were
Figure.
Naloxone differsfrom oxymorphone by the substitution of an aIlyI groupfor the methyl group (arrows).
t
'1
~H2CH - CH2
H
H
0 Naloxone
~H3
1152
HCL HO
0
O•
RESULTS
All samples, both preadministration and postadministralion, were negative for opiates and other drugs. The absorbance change, as described above, was compared with a calibrator cutoff level established by running controis at the beginning of the testing day. All samples fell below the cutoff level for a positive test. In addition, the absorbance changes of the pretest samples, compared with all postingestion samples, were not significantly different. DISCUSSION
HCk HO
obtained. One dose of 2 mg naloxone and then a 10-mL normal saline flush were given to all subjects. Three minutes later another dose, either 2 mg naloxone or an equivalent volume of normal saline, and a 10-mL normal saline flush were given. The 4-mg dose was used in seven study subjects to duplicate the clinical scenario of a partial responder or nonresponder in whom opiate toxicity was suspected. Urine samples were obtained at 30 minutes, 6 hours, and 48 hours after naloxone administration. Screens were performed using the Syva enzyme-multiplied immunoassay technique (EMIT) dau | (drugs of abuse urine) (Syva Co, San Jose, California) opiate assay and the Syva ETS | (EMIT Testing System) automated analyzer system. The EMIT dau opiate assay (Syva Co) is a homogeneous immunoassay technique used for analysis of specific opiate metabolites in urine. The assay is based on antibody binding-site competition between opiate drug metabolites in the urine and opiate metabolites labeled with glucose6-phosphate dehydrogenase, Enzyme activity is inhibited on binding to the antibody; therefore, the drug metabolite concentration in the sample can be measured in terms of enzyme activity Active enzyme converts oxidized nicotinamide adenine dinucleotide to reduced nicotinamide adenine dinucleotide, resulting in an absorbance change that is measured spectrophotometrically 4
Naloxone was introduced in 1967 and has found widespread use in emergency and inpatient settings. Standard emergency medicine and toxicology texts 5-7 advocate the use of 0.4 to 2.0 mg IV naloxone for altered mental status or suspected opiate toxicity Naloxone also is used commonly for postoperative narcotic depression. Naloxone is a competitive antagonist of all three narcotic receptors and is devoid of agonist activity An IV dose of 0.4 mg has been shown to penetrate the cerebrospinal fluid rapidly, followed by a decline in brain levels of 50% in 1 hour. 8-1~
ANNALS OF EMERGENCY MEDICINE
24:6
DECEMBER 1994
NALOXONE Storrow et al
Naloxone is related structurally to oxymorphone; the difference lies in the substitution of an allyl group for the methyl group on the nitrogen atom. Naloxone is metabolized rapidly in the liver, primarily by conjugation to glucuronide. Other metabolites included 8-dihydro-14hydroxynormorphine (reduced naloxone) and 7,8-dihydro-14-hydroxynormorphinone (dealkylated naloxone). Naloxone and its metabolites are partially excreted in the urine over several days; approximately 70% of an IV dose is excreted in normal subjects in 72 hours. 3 Despite its similarity to oxymorphone and its excretion time of several days, the possibility that naloxone could alter a subsequent UDS has not been reported. This information would be useful to caretakers of patients given naloxone, whether in an emergency setting or after hospital admission. In addition, some patients may receive naloxone in the ED before discharge, only to later undergo toxicologic screening for an unrelated reason. The military has long-term experience with random UDS. Recently, much attention has been given to employee and athletic screening. Concern has been raised that food substances, such as poppy seeds, 11 and medications, such as dextromethorphan, may interfere with the opiate assay Naloxone may receive the same attention. Identification of a positive opiate by urine EMIT testing is straightforward. More difficult, however, is identification of the specific opiate responsible. More sophisticated laboratories use thin-layer chromatography to identify the specific drug after the opiate screen is positive by EMIT testing. This is often unsuccessful if the opiate is present at a Iow concentration. A limitation of our study was the small sample size. As a pilot study, it underscores the need for additional work to increase the power of its implications. It is important to note that our study was specific to the Syva EMIT urine testing system. While this is a common method used worldwide, there are other systems used to evaluate drugs in urine. For example, the Abbott ADX system (Abbott Laboratories, Abbott Park, Illinois) lists naloxone as a possible cross-reactant with opiates.
REFERENCES 1. American Hospital FormularyService: Opiate antagonists, in McEvoy GK (ed): American Hospital FormularyService Drug Information. Bethesda, Maryland, American Society of Hospital Pharmacists, Inc, 1991, p 1257 1259. 2. Weinstein SH, Pfeffer M, $chor JM, et al: Metabolites of naloxone in human urine. J Pharm Sci 1971;60:1567-1568. 3. FishmanJ, Rof~arg H, Hellman L: Disposition of naloxone-7,8-3Hin normal and narcoticdependent men. J Pharm Exp Thor1973;187:575-580. 4. Syva Company:Emit~ dauTM Opiate Assay (monograph).Syva Co, San Jose, California, t991. 5. Weisman RS: Naloxone, in Goldfrank LR, Flomenbaum NE, Lewin NA, et al (eds): Goldfrank's ToxicologicEmergencies,ed 4. Norwalk, Connecticut,Appleton and Lange, 1990, p 444-445. 6. Allen T: Narcotics, in Rosen P, Barkin RM, Braen GR, et al (eds): EmergencyMedicine Conceptsand Clinical Practice, ed 3. St Louis, Mosby-Year Book, 1992, p 2603-2017. 7. Henry GL: Comaand altered states of consciousness,in Tintinalli JE, Krome RL, Ruiz E (eds): EmergencyMedicine: A ComprehensiveStudy Guide, ed 3. New York, McGraw-Hill Inc, 1992, p 150-158. 8. Berkowitz BA, Ngai SH, HempsteadJ, et al: Disposition of naloxone: Use of a new radioimmunoassay. J Pharm Exp Ther1975;195:499-504. 9. Ngai SH, Berkowitz BA, Yang JC, et al: Pharmacokineticsof naloxone in rats and in man: Basis for its potency and short duration of action Anesthesiology 1976;44:398-401. 10. Aitkenhead AR, Oerbyshire DR, PinneckCA, et al: Pharmacokineticsof intravenous naloxene in healthy volunteers. Anesthesiology1984;61:A381. 11. Selavka CM: Poppy-seedpositives: Perilous pastries. JForens Sci1991;36:685-696. The authors thank Robert She& RN; Cindy Bratt, RN; and Kelly Smith for their help with the technical aspects of this study.
Reprint no. 47/1159935 Address for reprints: Alan B Storrow, MD Wilford Hall Medical Center/PSAE Departmentof EmergencyMedicine 2200 BergquistDrive, Suite 1 LackTandAir ForceBase San Antonio, Texas78236-5300 210-670-7084 Fax 210-670-7649
CONCLUSION
Because naloxone hydrochloride is structurally similar to oxymorphone and its metabofites are excreted in human urine over several days, its potential to cause a false-positive opiate screen on standard urine drug screens is of concern. In our study, naloxone was not associated with a positive EMIT urine screen up to 48 hours after administration.
DECEMBER 1994
24:6
ANNALS OF EMERGENCY MEDICINE
1 1 53
D o e s Naloxone Cause a Positive Urine Opiate Screen? From the Departments of Emergency Medicine* and Pathology, t Wilford Hall Medical Center, San Antonio, Texas. Received for publication January 21, 1994. Revision received April 2 7, 1994. Accepted for publication May 6, 1994.
Alan B Storrow, MD*
Study objective: Todetermine whether the excreted metabo-
Frank H Wians, Jr, PhD, MT
lites of naloxone hydrochloride cause positive urine toxicologic screens for opiates.
(ASCP), DABCCt Stephen L Mikkelsen, MS, MT (ASCPp John Norton, BA, MT (ASCP)t
Presented at the American College of Emergency Physicians Research Forum, San Diego, California, March 1994; and at the Tri-Service Symposium in Emergency Medicine, San Antonio, Texas, April 1993. The opinions or assertions contained herein are those of the authors and should not be construed as official or as representing the opinions of the Department of the Air Force, Department of the Army, or the Department of Defense. Copyright 9 by the American College of Emergency Physicians.
Design: Prospective, randomized, double-blinded human protocol.
Setting: Urban Level I military emergency department. Participants: Fourteen adult volunteers who took no routine medications, were not pregnant, had no known sensitivity to
naloxone,and who were negative for a pretest urine and serum toxicologic screen. Interventions: We administered either 2 or 4 mg IV naloxone to 14 subjects. Urine drug screening was obtained before administration and at 60 minutes, 6 hours, and 48 hours after administration. Results: All urine drug screens using the enzyme-multiplied immunoassay technique were negative for opiates at both dosage levels. The sample size of 14 yielded a power of more than .99 to detect the difference between positive and negative samples. Conclusion: Although the metabolites of naloxone hydrochloride are similar in structure to oxymorphone and are excreted in human urine for several days, naloxone was not associated with a positive enzymatic urine screen for opiates. [Storrow AB, Wians FH Jr, Mikkelsen SL, Norton J: Does naloxone cause a positive urine opiate screen? Ann EmergMed December 1994;24:1151-1153.]
DECEMBER 1994 24:6 ANNALS OF EMERGENCYMEDICINE
1151
NALOXONE Storrow et al
i
INTRODUCTION
Naloxone hydrochloride has found widespread use for its opiate antagonist activity and excellent safety profile. It is given routinely to patients with acute alterations in mental status or with suspected opiate toxicity It is a synthetic congener of oxymorphone because of the replacement of a methyl group for an allyl group (Figure). 1 Naloxone is conjugated, dealkylated, and reduced in the liver to three compounds. 2 It requires up to 72 hours to be 70% eliminated by the kidney 3 Despite the structural similarity to opiates and the common use of urine drug screening (UDS) after naloxone administration, the effect of naloxone on UDS has not been reported. Furthermore, the use of UDS in the military and corporate sector makes the implication of a faulty result all the more grave. We conducted a study to determine the effect of IV naloxone use on urine opiate screening. MATERIALS AND METHODS
Our study protocol was approved by the Wilford Hall Medical Center Institutional Review Committee. Fourteen healthy, adult volunteers aged 18 to 55 years (mean, 29.1 years; SD, 3.1 years) underwent the administration of either 2 or 4 mg IV naloxone. Exclusion criteria included the ingestion of any medication within 72 hours before the study; a positive urine or serum drug screen; pregnancy; or underlying pulmonary, cardiac, renal, neurologic, or psychiatric disease. Each volunteer underwent the placement of an IV heparin lock after initial urine and serum samples were
Figure.
Naloxone differsfrom oxymorphone by the substitution of an aIlyI groupfor the methyl group (arrows).
t
'1
~H2CH - CH2
H
H
0 Naloxone
~H3
1152
HCL HO
0
O•
RESULTS
All samples, both preadministration and postadministralion, were negative for opiates and other drugs. The absorbance change, as described above, was compared with a calibrator cutoff level established by running controis at the beginning of the testing day. All samples fell below the cutoff level for a positive test. In addition, the absorbance changes of the pretest samples, compared with all postingestion samples, were not significantly different. DISCUSSION
HCk HO
obtained. One dose of 2 mg naloxone and then a 10-mL normal saline flush were given to all subjects. Three minutes later another dose, either 2 mg naloxone or an equivalent volume of normal saline, and a 10-mL normal saline flush were given. The 4-mg dose was used in seven study subjects to duplicate the clinical scenario of a partial responder or nonresponder in whom opiate toxicity was suspected. Urine samples were obtained at 30 minutes, 6 hours, and 48 hours after naloxone administration. Screens were performed using the Syva enzyme-multiplied immunoassay technique (EMIT) dau | (drugs of abuse urine) (Syva Co, San Jose, California) opiate assay and the Syva ETS | (EMIT Testing System) automated analyzer system. The EMIT dau opiate assay (Syva Co) is a homogeneous immunoassay technique used for analysis of specific opiate metabolites in urine. The assay is based on antibody binding-site competition between opiate drug metabolites in the urine and opiate metabolites labeled with glucose6-phosphate dehydrogenase, Enzyme activity is inhibited on binding to the antibody; therefore, the drug metabolite concentration in the sample can be measured in terms of enzyme activity Active enzyme converts oxidized nicotinamide adenine dinucleotide to reduced nicotinamide adenine dinucleotide, resulting in an absorbance change that is measured spectrophotometrically 4
Naloxone was introduced in 1967 and has found widespread use in emergency and inpatient settings. Standard emergency medicine and toxicology texts 5-7 advocate the use of 0.4 to 2.0 mg IV naloxone for altered mental status or suspected opiate toxicity Naloxone also is used commonly for postoperative narcotic depression. Naloxone is a competitive antagonist of all three narcotic receptors and is devoid of agonist activity An IV dose of 0.4 mg has been shown to penetrate the cerebrospinal fluid rapidly, followed by a decline in brain levels of 50% in 1 hour. 8-1~
ANNALS OF EMERGENCY MEDICINE
24:6
DECEMBER 1994
NALOXONE Storrow et al
Naloxone is related structurally to oxymorphone; the difference lies in the substitution of an allyl group for the methyl group on the nitrogen atom. Naloxone is metabolized rapidly in the liver, primarily by conjugation to glucuronide. Other metabolites included 8-dihydro-14hydroxynormorphine (reduced naloxone) and 7,8-dihydro-14-hydroxynormorphinone (dealkylated naloxone). Naloxone and its metabolites are partially excreted in the urine over several days; approximately 70% of an IV dose is excreted in normal subjects in 72 hours. 3 Despite its similarity to oxymorphone and its excretion time of several days, the possibility that naloxone could alter a subsequent UDS has not been reported. This information would be useful to caretakers of patients given naloxone, whether in an emergency setting or after hospital admission. In addition, some patients may receive naloxone in the ED before discharge, only to later undergo toxicologic screening for an unrelated reason. The military has long-term experience with random UDS. Recently, much attention has been given to employee and athletic screening. Concern has been raised that food substances, such as poppy seeds, 11 and medications, such as dextromethorphan, may interfere with the opiate assay Naloxone may receive the same attention. Identification of a positive opiate by urine EMIT testing is straightforward. More difficult, however, is identification of the specific opiate responsible. More sophisticated laboratories use thin-layer chromatography to identify the specific drug after the opiate screen is positive by EMIT testing. This is often unsuccessful if the opiate is present at a Iow concentration. A limitation of our study was the small sample size. As a pilot study, it underscores the need for additional work to increase the power of its implications. It is important to note that our study was specific to the Syva EMIT urine testing system. While this is a common method used worldwide, there are other systems used to evaluate drugs in urine. For example, the Abbott ADX system (Abbott Laboratories, Abbott Park, Illinois) lists naloxone as a possible cross-reactant with opiates.
REFERENCES 1. American Hospital FormularyService: Opiate antagonists, in McEvoy GK (ed): American Hospital FormularyService Drug Information. Bethesda, Maryland, American Society of Hospital Pharmacists, Inc, 1991, p 1257 1259. 2. Weinstein SH, Pfeffer M, $chor JM, et al: Metabolites of naloxone in human urine. J Pharm Sci 1971;60:1567-1568. 3. FishmanJ, Rof~arg H, Hellman L: Disposition of naloxone-7,8-3Hin normal and narcoticdependent men. J Pharm Exp Thor1973;187:575-580. 4. Syva Company:Emit~ dauTM Opiate Assay (monograph).Syva Co, San Jose, California, t991. 5. Weisman RS: Naloxone, in Goldfrank LR, Flomenbaum NE, Lewin NA, et al (eds): Goldfrank's ToxicologicEmergencies,ed 4. Norwalk, Connecticut,Appleton and Lange, 1990, p 444-445. 6. Allen T: Narcotics, in Rosen P, Barkin RM, Braen GR, et al (eds): EmergencyMedicine Conceptsand Clinical Practice, ed 3. St Louis, Mosby-Year Book, 1992, p 2603-2017. 7. Henry GL: Comaand altered states of consciousness,in Tintinalli JE, Krome RL, Ruiz E (eds): EmergencyMedicine: A ComprehensiveStudy Guide, ed 3. New York, McGraw-Hill Inc, 1992, p 150-158. 8. Berkowitz BA, Ngai SH, HempsteadJ, et al: Disposition of naloxone: Use of a new radioimmunoassay. J Pharm Exp Ther1975;195:499-504. 9. Ngai SH, Berkowitz BA, Yang JC, et al: Pharmacokineticsof naloxone in rats and in man: Basis for its potency and short duration of action Anesthesiology 1976;44:398-401. 10. Aitkenhead AR, Oerbyshire DR, PinneckCA, et al: Pharmacokineticsof intravenous naloxene in healthy volunteers. Anesthesiology1984;61:A381. 11. Selavka CM: Poppy-seedpositives: Perilous pastries. JForens Sci1991;36:685-696. The authors thank Robert She& RN; Cindy Bratt, RN; and Kelly Smith for their help with the technical aspects of this study.
Reprint no. 47/1159935 Address for reprints: Alan B Storrow, MD Wilford Hall Medical Center/PSAE Departmentof EmergencyMedicine 2200 BergquistDrive, Suite 1 LackTandAir ForceBase San Antonio, Texas78236-5300 210-670-7084 Fax 210-670-7649
CONCLUSION
Because naloxone hydrochloride is structurally similar to oxymorphone and its metabofites are excreted in human urine over several days, its potential to cause a false-positive opiate screen on standard urine drug screens is of concern. In our study, naloxone was not associated with a positive EMIT urine screen up to 48 hours after administration.
DECEMBER 1994
24:6
ANNALS OF EMERGENCY MEDICINE
1 1 53