Clinical Case Study
Clinical Chemistry 60:12 1480–1485 (2014)
Drug Addiction or False Conviction? Marion L. Snyder1 and Stacy E.F. Melanson2*
CASE A 25-year-old woman with a history of multiple medical problems including a distal pancreatectomy and splenectomy 6 months earlier for pancreatic mass (solid pseudopapillary tumor with negative margins), systemic lupus erythematous (SLE),3 Crohn disease, and a history of alcohol abuse presented to her pain management physician with weakness, decreased appetite, worsening joint pain, abdominal pain, and diarrhea (five episodes per day, some visibly bloody). At presentation, her vital signs included temperature 97.1 °F, blood pressure 127/89 mmHg, and heart rate 97 beats/min. Physical exam was remarkable for hyperactive bowel sounds, diffuse joint pain, and periumbilical pain at the surgical incision site described as constant and gnawing and graded 8 out of 10. She was prescribed morphine and oxycodone (as needed) for pain; hydroxychloroquine and prednisone for SLE; and mesalamine, docusate, and infliximab for Crohn disease. She was referred to her gastroenterologist for management of her gastrointestinal complaints. Her dosages of prednisone and hydroxychloroquine were maintained to control her SLE. Pulse doses of steroids and a higher dose of prednisone were considered, but the risk of infection was determined to be too great. Before refilling her morphine and oxycodone prescriptions, her physician confirmed that her previous urine drug testing results showed the presence of her prescribed medications (and related metabolites), suggesting medication compliance, as well as no unexpected drugs. The physician also performed a pill count and documented her last dose of morphine (that morning) and oxycodone (3 days before). In addition, she was asked to complete a Screener and Opioid Assessment for Patients with Pain questionnaire (1 ), de-
1
LabSource, Greenville, SC; 2 Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA. * Address correspondence to this author at: Brigham and Women’s Hospital, 75 Francis St, Amory 2, Boston, MA 02115. Fax 617-731-4872; e-mail semelanson@ partners.org. Received October 1, 2013; accepted January 13, 2014. DOI: 10.1373/clinchem.2013.216861 © 2014 American Association for Clinical Chemistry 3 Nonstandard abbreviations: SLE, systemic lupus erythematous; 6-AM, 6-acetylmorphine.
1480
QUESTIONS TO CONSIDER 1. Why is urine drug testing used to monitor patients treated with opioids for chronic pain? 2. What are the limitations of immunoassays, particularly for monitoring medication compliance in patients treated for chronic pain? 3. What is the significance of the patient’s urine creatinine result? 4. Do this patient’s screening results indicate undisclosed heroin, buprenorphine, and/or fentanyl use?
signed to assess her risk of medication noncompliance and abuse. On the basis of her responses to the questionnaire, the pill count, and her previous consistent urine drug testing results, the physician felt she was at low risk for noncompliance and renewed her oxycodone and morphine prescriptions. Because her last urine drug testing was performed 5 months earlier, he requested that she also submit a new urine sample for testing. After 3 days, the physician viewed the patient’s most recent urine drug testing results, at which time only results for in-house testing were available (Table 1). The patient’s urine screened positive for 6-acetylmorphine (6-AM), a unique heroin metabolite, and buprenorphine. The fentanyl screen was unsatisfactory due to an interfering substance. All other screening results were negative. Adulterant testing was significant for a creatinine of ⬎600 mg/dL in a relatively darkly colored urine. Specific opioid testing by LC-MS/MS revealed the presence of morphine (⬎300 000 ng/mL) and hydromorphone (472 ng/mL). Codeine, hydrocodone, oxycodone, and oxymorphone were not detected. Reflexive tests to confirm the positive 6-AM and buprenorphine and the indeterminate fentanyl were ordered but pending. On the basis of the results available at the time, the physician was concerned that the patient might be abusing multiple undisclosed drugs, including heroin, buprenorphine, and/or fentanyl. He contacted the laboratory director for assistance in interpreting the unexpected urine drug testing results.
Clinical Case Study
Table 1. Patient’s urine drug testing results available at the time of laboratory consultation. Drug/drug class
Methodologya b
Cutoff (ng/mL)
Results (reference interval)
6-AM (heroin metabolite)
CEDIA
10
Positivec
Buprenorphine
CEDIA
10
Positivec
Fentanyl
EIA
2
Amphetamines
DRI
1000
Negative
Barbiturates
DRI
200
Negative
Benzodiazepines
CEDIA
200
Negative
Cannabinoids
DRI
20
Negative
Cocaine
DRI
150
Negative
Methadone
DRI
300
Negative
Methadone metabolite, EDDP
CEDIA
100
Negative
Tramadol
EIA
200
Negative
Codeine
LC-MS/MS
100
Negative
Hydrocodone
LC-MS/MS
100
Negative
Hydromorphone
LC-MS/MS
100
472 ng/mL
Morphine
LC-MS/MS
100
⬎300 000 ng/mL
Oxycodone
LC-MS/MS
100
Negative
Oxymorphone
LC-MS/MS
100
Negative
pH
Colorimetric
NA
6.5 (4–9)
Creatinine
Colorimetric
NA
⬎600 mg/dL (20–300 mg/dL)
Oxidants
Colorimetric
NA
Negative (negative)
Unsatisfactory, interfering substancec
a
DRI, CEDIA, and colorimetric assays are manufactured by Thermo Scientific (formerly Microgenics), and fentanyl and tramadol enzyme immunoassays are manufactured by Immunalysis Corp. b CEDIA, cloned enzyme donor immunoassay; DRI, Diagnostics Reagents Inc.; EDDP, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine; NA, not applicable. c Quantitative LC-MS/MS follow-up testing was ordered but pending at the time of initial consultation.
DISCUSSION Physicians managing patients with chronic pain have the difficult job of ensuring availability of opioids to patients with legitimate medical need while minimizing the potential for their misuse. The rate of opioid abuse continues to rise, and several studies have demonstrated high frequencies of undisclosed drug use and potential diversion in patients treated with opioids for chronic pain (2–5 ). To minimize these risks, physicians generally require that patients on opioid therapy agree to receive medications only from a single prescriber and not use nonprescribed medications or illicit drugs. Patient self-reporting of drug use is frequently unreliable, and external sources, such as urine drug testing, are important tools for monitoring patient compliance (1 ). The detection of prescribed drugs/metabolites and the absence of other nonprescribed or illicit drugs in the urine is reassuring because it suggests adherence to the patient’s treatment plan. Recently updated pain management practice guidelines now recommend that drug testing be per-
formed to identify use of undisclosed substances, uncover diversion of prescribed substances, and determine compliance with prescribed substances (1, 6 ). Urine is the preferred specimen because of its extended drug detection window and the noninvasive nature of sample collection. Initial drug screening is commonly performed with class-specific immunoassay panels. Positive screening results, and in some circumstances negative results, are then followed by a more sensitive and specific technique such as GC-MS or LC-MS/MS to identify and confirm the presence of specific drugs and metabolites (1, 6 ). Immunoassay-based drug screens are frequently used for medication compliance monitoring because they are rapid, inexpensive, automatable, and easily performed on point-of-care devices. Although these immunoassays have traditionally been the most commonly used tests to screen urine for drugs, they must be carefully evaluated because some have been shown to have poor sensitivity and specificity (1, 6 ). Not all drugs within a class will cross-react in the assays, or may do so only at high concentrations. Clinical Chemistry 60:12 (2014) 1481
Clinical Case Study Also, many currently available immunoassays are reported as positive only when the measured analyte is present in a concentration above a defined threshold. Thus, a negative result does not necessarily mean that the drug is not present, but that it is not present at a concentration above the defined threshold. Because of these limitations, patients on low or as-needed doses of medications and/or medications that do not cross-react well in the assays can have falsely negative screening results. Immunoassay interferences are also a concern. Antibodies used in the assays may have limited specificity for the targeted drug or drug class and exhibit cross-reactivity toward other closely related compounds. Patients maintained on chronic opioids are often prescribed high doses of potentially interfering medications and are at risk for false positives. For example, previous studies have demonstrated false positives with buprenorphine (7 ) and 6-AM immunoassays (Thermo Scientific, formerly Microgenics), owing to nonspecific cross-reactivity with other opioids including methadone, morphine, and tramadol. Hydroxychloroquine has also been shown to generate false-positive responses in the buprenorphine assay (8 ). Highly colored and/or concentrated urines can also be problematic for screening by immunoassays that rely on photometric readings. In some cases, patients treated with opioids may abstain from fluids to increase drug concentrations in their urine (i.e., simulate adherence to higher prescribed doses), increasing the likelihood of this type of interference. Drugs, metabolites, and/or additives in urine can also interfere with immunoassay performance if they have absorption peaks similar to that of the measured chromogen used in the assay. In our laboratory, we found that 4% of the samples tested by the fentanyl homogeneous enzyme immunoassay (Immunalysis Corp.) exhibit unacceptably high background absorbance at 340 nm, preventing a valid result from being obtained (9 ). Given the known limitations of immunoassays, laboratories may bypass immunoassay screening and opt for a more sensitive and/or specific front-line technique, such as GC-MS and LC-MS/MS. However, these methods are generally more complex and time consuming, and it may be difficult to obtain desired turnaround times, especially when this testing is performed by another laboratory. Use of oral fluid as a test matrix is also a promising alternative for monitoring recent medication compliance in pain management (10 ). Oral fluid collection can be performed under direct observation with reduced risk of sample adulteration. Unlike urine testing, there can be a close correspondence between drug and metabolite concentrations in 1482 Clinical Chemistry 60:12 (2014)
oral fluid and in blood. However, the unique characteristics of oral fluid must be taken into account when interpreting these results (10 ). The use of urine drug testing for monitoring medication compliance in pain management is continuing to grow. Given the complexities of urine drug testing and the importance of the results for clinical decision making, it is essential that physicians understand the methods used and their strengths and weaknesses and how to interpret the pattern of results in relation to the patients’ medications. Written and/or verbal consultations from laboratory professionals that take into account the patient’s prescribed medications, the immunoassay screening results, the concentrations of the parent drugs and their metabolites, and clinical history can be valuable to guide patient management. In addition to defining an effective mechanism for test interpretation, laboratorians need to work with their physicians to determine the best testing algorithm for monitoring medication compliance in their patients, taking into account turnaround time and most frequently prescribed medications. CASE RESOLUTION The presence of morphine and hydromorphone (a minor morphine metabolite, typically detected as ⬍5% of total morphine concentration) in the urine was consistent with the patient’s prescribed morphine. The lack of oxycodone and oxymorphone in the urine were consistent with the patient’s report that her last dose of oxycodone was 3 days before providing the urine sample (Table 1). Buprenorphine, its major metabolite, norbuprenorphine; 6-AM; and fentanyl and its major metabolite, norfentanyl, were all negative by LC-MS/ MS. The positive screening results for 6-AM and buprenorphine were most likely due to the presence of high levels of known interferences, morphine and hydroxychloroquine, in the patient’s urine, and were false positives (8 ). The nonspecific antibody crossreactivities in the buprenorphine and 6-AM assays were likely exacerbated by the fact that the sample was highly concentrated (urine creatinine ⬎600 mg/dL), yielding higher concentrations of interfering drugs. The photometric interference seen in the fentanyl assay is likely attributed to the fact that the sample was highly concentrated and relatively dark in color. After discussing the LC-MS/MS results with the laboratory director, the physician concluded that the patient was adherent with her opioid therapy. The physician continued the patient’s prescriptions with the plan to slowly decrease the frequency and dosage of morphine as her abdominal pain improved.
Clinical Case Study POINTS TO REMEMBER • Monitoring medication compliance in pain management is important to identify use of undisclosed substances, uncover diversion of prescribed medications, and establish compliance with prescribed therapy. • Use of immunoassay drug screens for monitoring medication compliance in patients treated for chronic pain can be limited by poor cross-reactivity for common drugs within the target drug classes and limited specificity for the targeted drugs or drug classes, as well as photometric interferences. As a result, false negatives, false positives, and optical errors are observed. • Positive immunoassay results, and in some instances, negative results, should be followed by a more specific and sensitive method such as LC-MS/MS or GC-MS. • Adulterant testing, particularly creatinine, can be helpful to understand unexpected test results and help explain observed interferences. In some cases, patients treated with opioids may abstain from fluids as indicated by an increased urine creatinine to increase drug concentrations in their urine and simulate adherence to higher prescribed doses. Urine dilution or substitution can be identified by an unusually low urine creatinine result. • Written and/or verbal consultations from laboratory professionals that take into account the patient’s prescribed medications, the immunoassay screening results, the concentrations of the parent drugs and their metabolites, and clinical history can be valuable to assist clinicians with result interpretation and guide patient management.
Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article. Authors’ Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.
References 1. Manchikanti L, Atluri S, Trescot AM, Giordano J. Monitoring opioid adherence in chronic pain patients: tools, techniques, and utility. Pain Physician 2008;11:S155– 80. 2. Katz NP, Sherburne S, Beach M, Rose RJ, Vielguth J, Bradley J, Fanciullo GJ. Behavioral monitoring and urine toxicology testing in patients receiving long-term opioid therapy. Anesth Analg 2003;97:1097–102. 3. Manchikanti L, Cash KA, Damron KS, Manchukonda R, Pampati V, McManus CD. Controlled substance abuse and illicit drug use in chronic pain patients: an evaluation of multiple variables. Pain Physician 2006;9:215–25. 4. Michna E, Jamison RN, Pham LD, et al. Urine toxicology screening among chronic pain patients on opioid therapy: frequency and predictability of abnormal findings. Clin J Pain 2007;23:173–9. 5. Zacny J, Bigelow G, Compton P, Foley K, Iguchi M, Sannerud C. College on Problems of Drug Dependence taskforce on prescription opioid non-medical use and abuse: position statement. Drug Alcohol Depend 2003;69:215–32. 6. Trescot AM, Helm S, Hansen H, et al. Opioids in the management of chronic non-cancer pain: an update of American Society of the Interventional Pain Physicians’ (ASIPP) Guidelines. Pain Physician 2008;11:S5–S62. 7. Pavlic M, Libiseller K, Grubwieser P, Rabl W. Cross-reactivity of the CEDIA buprenorphine assay with opiates: an Austrian phenomenon? Int J Legal Med 2005;119:378 – 81. 8. Melanson SE, Snyder ML, Jarolim P, Flood JG. A new highly specific buprenorphine immunoassay for monitoring buprenorphine compliance and abuse. J Anal Toxicol 2012;36:201– 6. 9. Snyder ML, Jarolim P, Melanson SE. A new automated urine fentanyl immunoassay: technical performance and clinical utility for monitoring fentanyl compliance. Clin Chim Acta 2011;412:946 –51. 10. Cone EJ, Huestis MA. Interpretation of oral fluid tests for drugs of abuse. Ann NY Acad Sci 2007;1098:51–103.
Commentary B.J. Magnani1,2*
This case illustrates the importance of understanding the limitations of immunoassay screening for drugs of abuse and the need for quantitative confirmation test-
1
Department of Pathology and Laboratory Medicine, Tufts Medical Center, and Department of Anatomic and Clinical Pathology, Tufts University School of Medicine, Boston, MA. * Address correspondence to the author at: Department of Pathology and Laboratory Medicine, Tufts Medical Center, 800 Washington St., Box 115, Boston, MA 02111. E-mail [email protected]. Received April 7, 2014; accepted April 14, 2014. DOI: 10.1373/clinchem.2014.224550 © 2014 American Association for Clinical Chemistry 2
ing in patients using opioid medications for chronic noncancer pain therapy (1, 2 ). Specific guidelines written to help clinicians who prescribe opioids for pain management have recognized the urine drug screen as an aid in establishing compliance with the prescription regimen. The role of the urine drug test as an adjunct to pain therapy monitoring is that it primarily supplements pill counts and behavioral monitoring and identifies problems that would have otherwise gone undetected. Urine drug testing is an objective measure that identifies the nonuse of prescribed drugs and the use of nonprescribed drugs, illicit drugs, and alcohol. Clinical Chemistry 60:12 (2014) 1483
Clinical Chemistry 60:12 1480–1485 (2014)
Drug Addiction or False Conviction? Marion L. Snyder1 and Stacy E.F. Melanson2*
CASE A 25-year-old woman with a history of multiple medical problems including a distal pancreatectomy and splenectomy 6 months earlier for pancreatic mass (solid pseudopapillary tumor with negative margins), systemic lupus erythematous (SLE),3 Crohn disease, and a history of alcohol abuse presented to her pain management physician with weakness, decreased appetite, worsening joint pain, abdominal pain, and diarrhea (five episodes per day, some visibly bloody). At presentation, her vital signs included temperature 97.1 °F, blood pressure 127/89 mmHg, and heart rate 97 beats/min. Physical exam was remarkable for hyperactive bowel sounds, diffuse joint pain, and periumbilical pain at the surgical incision site described as constant and gnawing and graded 8 out of 10. She was prescribed morphine and oxycodone (as needed) for pain; hydroxychloroquine and prednisone for SLE; and mesalamine, docusate, and infliximab for Crohn disease. She was referred to her gastroenterologist for management of her gastrointestinal complaints. Her dosages of prednisone and hydroxychloroquine were maintained to control her SLE. Pulse doses of steroids and a higher dose of prednisone were considered, but the risk of infection was determined to be too great. Before refilling her morphine and oxycodone prescriptions, her physician confirmed that her previous urine drug testing results showed the presence of her prescribed medications (and related metabolites), suggesting medication compliance, as well as no unexpected drugs. The physician also performed a pill count and documented her last dose of morphine (that morning) and oxycodone (3 days before). In addition, she was asked to complete a Screener and Opioid Assessment for Patients with Pain questionnaire (1 ), de-
1
LabSource, Greenville, SC; 2 Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA. * Address correspondence to this author at: Brigham and Women’s Hospital, 75 Francis St, Amory 2, Boston, MA 02115. Fax 617-731-4872; e-mail semelanson@ partners.org. Received October 1, 2013; accepted January 13, 2014. DOI: 10.1373/clinchem.2013.216861 © 2014 American Association for Clinical Chemistry 3 Nonstandard abbreviations: SLE, systemic lupus erythematous; 6-AM, 6-acetylmorphine.
1480
QUESTIONS TO CONSIDER 1. Why is urine drug testing used to monitor patients treated with opioids for chronic pain? 2. What are the limitations of immunoassays, particularly for monitoring medication compliance in patients treated for chronic pain? 3. What is the significance of the patient’s urine creatinine result? 4. Do this patient’s screening results indicate undisclosed heroin, buprenorphine, and/or fentanyl use?
signed to assess her risk of medication noncompliance and abuse. On the basis of her responses to the questionnaire, the pill count, and her previous consistent urine drug testing results, the physician felt she was at low risk for noncompliance and renewed her oxycodone and morphine prescriptions. Because her last urine drug testing was performed 5 months earlier, he requested that she also submit a new urine sample for testing. After 3 days, the physician viewed the patient’s most recent urine drug testing results, at which time only results for in-house testing were available (Table 1). The patient’s urine screened positive for 6-acetylmorphine (6-AM), a unique heroin metabolite, and buprenorphine. The fentanyl screen was unsatisfactory due to an interfering substance. All other screening results were negative. Adulterant testing was significant for a creatinine of ⬎600 mg/dL in a relatively darkly colored urine. Specific opioid testing by LC-MS/MS revealed the presence of morphine (⬎300 000 ng/mL) and hydromorphone (472 ng/mL). Codeine, hydrocodone, oxycodone, and oxymorphone were not detected. Reflexive tests to confirm the positive 6-AM and buprenorphine and the indeterminate fentanyl were ordered but pending. On the basis of the results available at the time, the physician was concerned that the patient might be abusing multiple undisclosed drugs, including heroin, buprenorphine, and/or fentanyl. He contacted the laboratory director for assistance in interpreting the unexpected urine drug testing results.
Clinical Case Study
Table 1. Patient’s urine drug testing results available at the time of laboratory consultation. Drug/drug class
Methodologya b
Cutoff (ng/mL)
Results (reference interval)
6-AM (heroin metabolite)
CEDIA
10
Positivec
Buprenorphine
CEDIA
10
Positivec
Fentanyl
EIA
2
Amphetamines
DRI
1000
Negative
Barbiturates
DRI
200
Negative
Benzodiazepines
CEDIA
200
Negative
Cannabinoids
DRI
20
Negative
Cocaine
DRI
150
Negative
Methadone
DRI
300
Negative
Methadone metabolite, EDDP
CEDIA
100
Negative
Tramadol
EIA
200
Negative
Codeine
LC-MS/MS
100
Negative
Hydrocodone
LC-MS/MS
100
Negative
Hydromorphone
LC-MS/MS
100
472 ng/mL
Morphine
LC-MS/MS
100
⬎300 000 ng/mL
Oxycodone
LC-MS/MS
100
Negative
Oxymorphone
LC-MS/MS
100
Negative
pH
Colorimetric
NA
6.5 (4–9)
Creatinine
Colorimetric
NA
⬎600 mg/dL (20–300 mg/dL)
Oxidants
Colorimetric
NA
Negative (negative)
Unsatisfactory, interfering substancec
a
DRI, CEDIA, and colorimetric assays are manufactured by Thermo Scientific (formerly Microgenics), and fentanyl and tramadol enzyme immunoassays are manufactured by Immunalysis Corp. b CEDIA, cloned enzyme donor immunoassay; DRI, Diagnostics Reagents Inc.; EDDP, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine; NA, not applicable. c Quantitative LC-MS/MS follow-up testing was ordered but pending at the time of initial consultation.
DISCUSSION Physicians managing patients with chronic pain have the difficult job of ensuring availability of opioids to patients with legitimate medical need while minimizing the potential for their misuse. The rate of opioid abuse continues to rise, and several studies have demonstrated high frequencies of undisclosed drug use and potential diversion in patients treated with opioids for chronic pain (2–5 ). To minimize these risks, physicians generally require that patients on opioid therapy agree to receive medications only from a single prescriber and not use nonprescribed medications or illicit drugs. Patient self-reporting of drug use is frequently unreliable, and external sources, such as urine drug testing, are important tools for monitoring patient compliance (1 ). The detection of prescribed drugs/metabolites and the absence of other nonprescribed or illicit drugs in the urine is reassuring because it suggests adherence to the patient’s treatment plan. Recently updated pain management practice guidelines now recommend that drug testing be per-
formed to identify use of undisclosed substances, uncover diversion of prescribed substances, and determine compliance with prescribed substances (1, 6 ). Urine is the preferred specimen because of its extended drug detection window and the noninvasive nature of sample collection. Initial drug screening is commonly performed with class-specific immunoassay panels. Positive screening results, and in some circumstances negative results, are then followed by a more sensitive and specific technique such as GC-MS or LC-MS/MS to identify and confirm the presence of specific drugs and metabolites (1, 6 ). Immunoassay-based drug screens are frequently used for medication compliance monitoring because they are rapid, inexpensive, automatable, and easily performed on point-of-care devices. Although these immunoassays have traditionally been the most commonly used tests to screen urine for drugs, they must be carefully evaluated because some have been shown to have poor sensitivity and specificity (1, 6 ). Not all drugs within a class will cross-react in the assays, or may do so only at high concentrations. Clinical Chemistry 60:12 (2014) 1481
Clinical Case Study Also, many currently available immunoassays are reported as positive only when the measured analyte is present in a concentration above a defined threshold. Thus, a negative result does not necessarily mean that the drug is not present, but that it is not present at a concentration above the defined threshold. Because of these limitations, patients on low or as-needed doses of medications and/or medications that do not cross-react well in the assays can have falsely negative screening results. Immunoassay interferences are also a concern. Antibodies used in the assays may have limited specificity for the targeted drug or drug class and exhibit cross-reactivity toward other closely related compounds. Patients maintained on chronic opioids are often prescribed high doses of potentially interfering medications and are at risk for false positives. For example, previous studies have demonstrated false positives with buprenorphine (7 ) and 6-AM immunoassays (Thermo Scientific, formerly Microgenics), owing to nonspecific cross-reactivity with other opioids including methadone, morphine, and tramadol. Hydroxychloroquine has also been shown to generate false-positive responses in the buprenorphine assay (8 ). Highly colored and/or concentrated urines can also be problematic for screening by immunoassays that rely on photometric readings. In some cases, patients treated with opioids may abstain from fluids to increase drug concentrations in their urine (i.e., simulate adherence to higher prescribed doses), increasing the likelihood of this type of interference. Drugs, metabolites, and/or additives in urine can also interfere with immunoassay performance if they have absorption peaks similar to that of the measured chromogen used in the assay. In our laboratory, we found that 4% of the samples tested by the fentanyl homogeneous enzyme immunoassay (Immunalysis Corp.) exhibit unacceptably high background absorbance at 340 nm, preventing a valid result from being obtained (9 ). Given the known limitations of immunoassays, laboratories may bypass immunoassay screening and opt for a more sensitive and/or specific front-line technique, such as GC-MS and LC-MS/MS. However, these methods are generally more complex and time consuming, and it may be difficult to obtain desired turnaround times, especially when this testing is performed by another laboratory. Use of oral fluid as a test matrix is also a promising alternative for monitoring recent medication compliance in pain management (10 ). Oral fluid collection can be performed under direct observation with reduced risk of sample adulteration. Unlike urine testing, there can be a close correspondence between drug and metabolite concentrations in 1482 Clinical Chemistry 60:12 (2014)
oral fluid and in blood. However, the unique characteristics of oral fluid must be taken into account when interpreting these results (10 ). The use of urine drug testing for monitoring medication compliance in pain management is continuing to grow. Given the complexities of urine drug testing and the importance of the results for clinical decision making, it is essential that physicians understand the methods used and their strengths and weaknesses and how to interpret the pattern of results in relation to the patients’ medications. Written and/or verbal consultations from laboratory professionals that take into account the patient’s prescribed medications, the immunoassay screening results, the concentrations of the parent drugs and their metabolites, and clinical history can be valuable to guide patient management. In addition to defining an effective mechanism for test interpretation, laboratorians need to work with their physicians to determine the best testing algorithm for monitoring medication compliance in their patients, taking into account turnaround time and most frequently prescribed medications. CASE RESOLUTION The presence of morphine and hydromorphone (a minor morphine metabolite, typically detected as ⬍5% of total morphine concentration) in the urine was consistent with the patient’s prescribed morphine. The lack of oxycodone and oxymorphone in the urine were consistent with the patient’s report that her last dose of oxycodone was 3 days before providing the urine sample (Table 1). Buprenorphine, its major metabolite, norbuprenorphine; 6-AM; and fentanyl and its major metabolite, norfentanyl, were all negative by LC-MS/ MS. The positive screening results for 6-AM and buprenorphine were most likely due to the presence of high levels of known interferences, morphine and hydroxychloroquine, in the patient’s urine, and were false positives (8 ). The nonspecific antibody crossreactivities in the buprenorphine and 6-AM assays were likely exacerbated by the fact that the sample was highly concentrated (urine creatinine ⬎600 mg/dL), yielding higher concentrations of interfering drugs. The photometric interference seen in the fentanyl assay is likely attributed to the fact that the sample was highly concentrated and relatively dark in color. After discussing the LC-MS/MS results with the laboratory director, the physician concluded that the patient was adherent with her opioid therapy. The physician continued the patient’s prescriptions with the plan to slowly decrease the frequency and dosage of morphine as her abdominal pain improved.
Clinical Case Study POINTS TO REMEMBER • Monitoring medication compliance in pain management is important to identify use of undisclosed substances, uncover diversion of prescribed medications, and establish compliance with prescribed therapy. • Use of immunoassay drug screens for monitoring medication compliance in patients treated for chronic pain can be limited by poor cross-reactivity for common drugs within the target drug classes and limited specificity for the targeted drugs or drug classes, as well as photometric interferences. As a result, false negatives, false positives, and optical errors are observed. • Positive immunoassay results, and in some instances, negative results, should be followed by a more specific and sensitive method such as LC-MS/MS or GC-MS. • Adulterant testing, particularly creatinine, can be helpful to understand unexpected test results and help explain observed interferences. In some cases, patients treated with opioids may abstain from fluids as indicated by an increased urine creatinine to increase drug concentrations in their urine and simulate adherence to higher prescribed doses. Urine dilution or substitution can be identified by an unusually low urine creatinine result. • Written and/or verbal consultations from laboratory professionals that take into account the patient’s prescribed medications, the immunoassay screening results, the concentrations of the parent drugs and their metabolites, and clinical history can be valuable to assist clinicians with result interpretation and guide patient management.
Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article. Authors’ Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.
References 1. Manchikanti L, Atluri S, Trescot AM, Giordano J. Monitoring opioid adherence in chronic pain patients: tools, techniques, and utility. Pain Physician 2008;11:S155– 80. 2. Katz NP, Sherburne S, Beach M, Rose RJ, Vielguth J, Bradley J, Fanciullo GJ. Behavioral monitoring and urine toxicology testing in patients receiving long-term opioid therapy. Anesth Analg 2003;97:1097–102. 3. Manchikanti L, Cash KA, Damron KS, Manchukonda R, Pampati V, McManus CD. Controlled substance abuse and illicit drug use in chronic pain patients: an evaluation of multiple variables. Pain Physician 2006;9:215–25. 4. Michna E, Jamison RN, Pham LD, et al. Urine toxicology screening among chronic pain patients on opioid therapy: frequency and predictability of abnormal findings. Clin J Pain 2007;23:173–9. 5. Zacny J, Bigelow G, Compton P, Foley K, Iguchi M, Sannerud C. College on Problems of Drug Dependence taskforce on prescription opioid non-medical use and abuse: position statement. Drug Alcohol Depend 2003;69:215–32. 6. Trescot AM, Helm S, Hansen H, et al. Opioids in the management of chronic non-cancer pain: an update of American Society of the Interventional Pain Physicians’ (ASIPP) Guidelines. Pain Physician 2008;11:S5–S62. 7. Pavlic M, Libiseller K, Grubwieser P, Rabl W. Cross-reactivity of the CEDIA buprenorphine assay with opiates: an Austrian phenomenon? Int J Legal Med 2005;119:378 – 81. 8. Melanson SE, Snyder ML, Jarolim P, Flood JG. A new highly specific buprenorphine immunoassay for monitoring buprenorphine compliance and abuse. J Anal Toxicol 2012;36:201– 6. 9. Snyder ML, Jarolim P, Melanson SE. A new automated urine fentanyl immunoassay: technical performance and clinical utility for monitoring fentanyl compliance. Clin Chim Acta 2011;412:946 –51. 10. Cone EJ, Huestis MA. Interpretation of oral fluid tests for drugs of abuse. Ann NY Acad Sci 2007;1098:51–103.
Commentary B.J. Magnani1,2*
This case illustrates the importance of understanding the limitations of immunoassay screening for drugs of abuse and the need for quantitative confirmation test-
1
Department of Pathology and Laboratory Medicine, Tufts Medical Center, and Department of Anatomic and Clinical Pathology, Tufts University School of Medicine, Boston, MA. * Address correspondence to the author at: Department of Pathology and Laboratory Medicine, Tufts Medical Center, 800 Washington St., Box 115, Boston, MA 02111. E-mail [email protected]. Received April 7, 2014; accepted April 14, 2014. DOI: 10.1373/clinchem.2014.224550 © 2014 American Association for Clinical Chemistry 2
ing in patients using opioid medications for chronic noncancer pain therapy (1, 2 ). Specific guidelines written to help clinicians who prescribe opioids for pain management have recognized the urine drug screen as an aid in establishing compliance with the prescription regimen. The role of the urine drug test as an adjunct to pain therapy monitoring is that it primarily supplements pill counts and behavioral monitoring and identifies problems that would have otherwise gone undetected. Urine drug testing is an objective measure that identifies the nonuse of prescribed drugs and the use of nonprescribed drugs, illicit drugs, and alcohol. Clinical Chemistry 60:12 (2014) 1483
